3,5-disubstituted-3H-imidazo[4,5-B]pyridine and 3,5-disubstituted-3H-[1,2,3]triazolo[4,5-B] pyridine compounds as modulators of protein kinases

ABSTRACT

The present invention provides, inter alia, compounds of formula I as protein kinase modulators, methods of preparing them, pharmaceutical compositions containing them and methods of treatment, prevention and/or amelioration of kinase mediated diseases or disorders with them.

This application is a continuation of U.S. patent application Ser. No.14/534,909, filed Nov. 6, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/891,961, filed May 10, 2013, now U.S. Pat. No.8,912,331, which is a continuation of U.S. patent application Ser. No.13/108,642, filed May 16, 2011, now U.S. Pat. No. 8,481,739, whichclaims the benefit of Indian Provisional Patent Application No.1377/CHE/2010, dated 17 May 2010 which is hereby incorporated byreference.

FIELD OF THE INVENTION

The present invention provides, inter alia, compounds of formula I asprotein kinase modulators, methods of preparing them, pharmaceuticalcompositions containing them and methods of treatment, prevention and/oramelioration of kinase mediated diseases or disorders with them.

BACKGROUND OF THE INVENTION

In the recent past immense research has been dedicated to the discoveryand understanding of the structure and functions of enzymes andbio-molecules associated with various diseases. One such important classof enzymes that has been the subject of extensive research is ProteinKinase.

In general, protein kinases represent a set of structurally relatedphosphoryl transferases, having conserved structures and catalyticfunctions. These enzymes modify proteins by chemically adding phosphategroups (phosphorylation). Phosphorylation involves the removal of aphosphate group from ATP and covalently attaching it to amino acids thathave a free hydroxyl group such as serine, threonine or tyrosine.Phosphorylation usually results in a functional change of the targetprotein (substrate) by altering enzyme activity, cellular localizationor association with other proteins. Up to 30% of all proteins may bemodified by kinase activity.

This class of proteins are classified into subsets depending upon thesubstrate they act upon such as tyrosine kinase, serine/theroninekinase, histidine kinase and the like. These proteins can also beclassified based on their localization into receptor tyrosine kinases(RTKs) or non-receptor tyrosine kinases.

Receptor tyrosine kinases (RTKs) have an extracellular portion, atransmembrane domain, and an intracellular portion, while non-receptortyrosine kinases are entirely intracellular. Receptor tyrosine kinasemediated signal transduction is typically initiated by an extracellularinteraction with a specific growth factor (ligand), followed by receptordimerization, stimulation of the intrinsic protein tyrosine kinaseactivity, and phosphorylation of amino acid residues. The ensuingconformational change leads to the formation of complexes with aspectrum of cytoplasmic signalling molecules and facilitates a myriad ofresponses such as cell division, differentiation, metabolic effects, andchanges in the extracellular microenvironment.

At present, at least twenty (20) distinct RTK subfamilies have beenidentified. One subfamily of the RTKs is designated as the Met subfamily(c-Met, Ron and Sea). For a detailed discussion of protein kinases, see,Plowman et al., DN&P 7(6): 334-339, 1994, Blume-Jensen, P. et al.,Nature 2001, 411(6835):355-365 and Manning, G. et al., Science. 2002,298(5600): 1912-1934.

Kinases have also been classified either based on the pathway or thediseases in which they are involved(visit:www.reactionbiology.com/pages/kinase.htm). c-Met has beenidentified as involved in oncogenesis.

Protein kinases exert their physiological functions throughphosphorylation of proteins (or substrates) thereby modulating thecellular activities of the substrate in various biological contexts.Protein kinases are known to control a wide variety of biologicalprocesses such as cell growth, survival and differentiation, organformation and morphogenesis, neovascularisation, tissue repair andregeneration. In addition to their functions in normal tissues/organs,many protein kinases also play specialized roles in a host of humandiseases including cancer. A subset of protein kinases (also referred toas oncogenic protein kinases), when dysregulated, can cause tumorformation and growth and contribute to tumor maintenance and progression(Blume-Jensen P et al, Nature 2001, 411(6835):355-365). Thus far,oncogenic protein kinases represent one of the largest and mostattractive groups of protein targets for therapeutic intervention anddrug development.

Both receptor and non-receptor protein kinases have been found to beattractive targets for small molecule drug discovery due to their impacton cell physiology and signalling. Dysregulation of protein kinaseactivity thus leads to altered cellular responses including uncontrolledcell growth associated with cancer. In addition to oncologicalindications, altered kinase signalling is implicated in numerous otherpathological diseases. These include, but are not limited toimmunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases.

A significant number of tyrosine kinases (both receptor and nonreceptor)are associated with cancer (see Madhusudan S, Ganesan TS. Tyrosinekinase inhibitors in cancer therapy. Clin. Biochem. 2004,37(7):618-35.). Clinical studies suggest that over expression ordysregulation of tyrosine kinases may also be of prognostic value. Forexample, members of the HER family of RTKs have been implicated inbreast, colorectal, head and neck and lung cancer. Mutation of c-Kittyrosine kinase is associated with decreased survival ingastrointestinal stromal tumors (GIST). In acute myelogenous leukemia,Flt-3 mutation predicts shorter disease free survival. VEGFR expression,which is important for tumor angiogenesis, is associated with a lowersurvival rate in lung cancer. Tie-1 kinase expression is inverselycorrelated to survival in gastric cancer. BCR-AbI expression is animportant predictor of response in chronic myelogenous leukemia whileSrc tyrosine kinase expression is co-related to the stage of colorectalcancer.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, the two key cellular processes needed for tumor growth andsurvival is an attractive goal for development of small-molecule drugs(Matter A. Drug Disc Technol 2001, 6, 1005-1024). Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularisation including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. Similarly, cellantiproliferative agents are desirable to slow or inhibit the growth oftumors.

Some of the kinases implicated in cancer are c-Met, RON (recepteurd'origine nantais) receptor, Vascular Endothelial Growth Factor (VEGF)receptor, Epidermal growth factor receptor kinase (EGF-R kinase), Ephreceptors, c-Kit, and Flt-3.

A number of small molecule kinase modulators have found their way intothe clinic which either act selectively on either one or multiplekinases. These include Gefitinib (AstraZeneca), a EGFR kinase inhibitor;Gleevec (Novartis), a dual c-Kit and AbI kinase inhibitor approved forthe treatment of Chronic Myeloid Leukemia (CML) and gastrointestinalstroma cancers; Dasatinib (BMS), a dual BCR/ABL and Src family tyrosinekinases inhibitor, and Sunitinib (Pfizer) a multi kinase inhibitortargeting PDGF-R, VEGF-R, RET, KIT(CD117), CSF-1R and flt-3.

The kinase, c-Met, is the prototypic member of a subfamily ofheterodimeric receptor tyrosine kinases (RTKs) which include Met, Ronand Sea (see Birchmeier, C. et al., Nat. Rev. Mol. Cell Biol. 2003,4(12):915-925; Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26). Expression of c-Met occurs in a wide variety of cell typesincluding epithelial, endothelial and mesenchymal cells where activationof the receptor induces cell migration, invasion, proliferation andother biological activities associated with “invasive cell growth.” Assuch, signal transduction through c-Met receptor activation isresponsible for many of the characteristics of tumor cells.

The only high affinity endogenous ligand for c-Met is the hepatocytegrowth factor (HGF), also known as scatter factor (SF). Binding of HGFto c-Met induces activation of the receptor via autophosphorylationresulting in an increase of receptor dependent signalling, whichpromotes cell growth and invasion. Both c-Met and HGF are widelyexpressed in a variety of organs, but their expression is normallyconfined to cells of epithelial and mesenchymal origin. Anti-HGFantibodies or HGF antagonists have been shown to inhibit tumormetastasis in vivo (See: Maulik et al Cytokine & Growth Factor Reviews2002, 13, 41-59). The biological functions of c-Met (or c-Met signallingpathway) in normal tissues and human malignancies such as cancer havebeen well documented (Christensen, J. G. et al., Cancer Lett. 2005,225(1): 1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292).

Tumor growth progression involves the recruitment of new blood vesselsinto the tumor as well as invasion, adhesion and proliferation ofmalignant cells. c-Met over expression has been demonstrated on a widevariety of tumor types including breast, colon, renal, lung, squamouscell myeloid leukemia, hemangiomas, melanomas, astrocytomas, andglioblastomas. Additionally activating mutations in the kinase domain ofc-Met have been identified in hereditary and sporadic renal papillomaand squamous cell carcinoma. See Maulik et al Cytokine & growth Factorreviews 2002, 13, 41-59; Longati et al Curr Drug Targets 2001, 2, 41-55;Funakoshi et al Clinica Chimica Acta 2003 1-23. Thus modulation of c-Metoffers an attractive opportunity to target key oncogenic processes thuslimiting cell proliferation, survival and metastasis.

Dysregulated c-Met pathway is linked to tumor formation, growth,maintenance and progression (Birchmeier, C. et al., Nat. Rev. Mol. Cell.Biol. 2003, 4(12):915-925; Boccaccio, C. et al., Nat. Rev. Cancer 2006,6(8):637-645; Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26). HGF and/or c-Met are over expressed in significant portions ofmost human cancers, and are often associated with poor clinical outcomessuch as more aggressive disease, disease progression, tumor metastasisand shortened patient survival. Further, patients with high levels ofHGF/c-Met proteins are more resistant to chemotherapy and radiotherapy.In addition to abnormal HGF/c-Met expression, the c-Met receptor canalso be activated in cancer patients through genetic mutations (bothgermline and somatic) and gene amplification. Although geneamplification and mutations are the most common genetic alterations thathave been reported in patients, the receptor can also be activated bydeletions, truncations, and gene rearrangement, as well as abnormalreceptor processing and defective negative regulatory mechanisms.

The various cancers in which c-Met is implicated include but are notlimited to carcinomas (e.g., bladder, breast, cervical,cholangiocarcinoma, colorectal, esophageal, gastric, head and neck,kidney, liver, lung, nasopharygeal, ovarian, pancreas, prostate,thyroid); musculoskeletal sarcomas (e.g., osteosarcaoma, synovialsarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g.,MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma); hematopoieticmalignancies (e.g., multiple myeloma, lymphomas, adult T cell leukemia,acute myelogenous leukemia, chronic myeloid leukemia); and otherneoplasms (e.g., glioblastomas, astrocytomas, melanoma, mesothelioma andWilm's tumor (www.vai.org/met/; Christensen, J. G. et al., Cancer Lett.2005, 225(1): 1-26). c-Met inhibitors may also be useful in preventativeand adjuvant therapy settings. In addition, certain cancers (e.g.,papillary renal cell carcinoma, and some gastric and lung cancers) maybe treated with c-Met inhibitors as they are believed to be driven byc-Met mutation/genetic alteration and dependent on c-Met for growth andsurvival. These cancers are expected to be sensitive to treatment.

The notion that activated c-Met contributes to tumor formation andprogression and could therefore be a potential target for effectivecancer intervention has been further validated by numerous preclinicalstudies (Birchmeier, C. et al., Nat. Rev. Mol. Cell Biol. 2003,4(12):915-925; Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26; Corso, S. et al., Trends in Mol. Med. 2005, 11(6):284-292). Forexample, studies have demonstrated that the tpr-met fusion gene, overexpression of c-Met, and activated c-Met mutations caused oncogenictransformation of various model cell lines and resulted in tumorformation and metastasis in mice. Conversely, significant anti-tumor andanti-metastasis activities have been demonstrated in vitro and in vivowith agents that specifically impair and/or block HGF/c-Met signalling.Those agents include anti-HGF and anti-c-Met antibodies, HGF peptideantagonists, decoy c-Met receptor, c-Met peptide antagonists, dominantnegative c-Met mutations, c-Met specific antisense oligonucleotides andribozymes, and selective small molecule c-Met kinase inhibitors(Christensen, J. G. et al., Cancer Lett. 2005, 225(1): 1-26). Inaddition to its established role in cancer, abnormal HGF/c-Metsignalling is also implicated in atherosclerosis, lung fibrosis, renalfibrosis and regeneration, liver diseases, allergic disorders,inflammatory and autoimmune disorders, cerebrovascular diseases,cardiovascular diseases, and conditions associated with organtransplantation. See Ma, H. et al., Atherosclerosis. 2002, 164(1):79-87;Crestani, B. et al., Lab. Invest. 2002, 82(8): 1015-1022; Sequra-Flores,A. A. et al., Rev. Gastroenterol. Mex. 2004, 69(4)243-250; Morishita, R.et al., Curr. Gene Ther. 2004, 4(2)199-206; Morishita, R. et al.,Endocr. J. 2002, 49(3)273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens.2002, 1 1 (1):23-30; Matsumoto, K. et al., Kidney Int. 2001,59(6):2023-2038; Balkovetz, D. F. et al., Int. Rev. Cytol. 1999,186:225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998,18(4)345-348; Koch, A. E. et al., Arthritis Rheum. 1996,39(9):1566-1575; Futamatsu, H. et al., Circ. Res. 2005, 96(8)823-830;Eguchi, S. et al., Clin. Transplant. 1999, 13(6)536-544.

c-Met is thus an attractive target from a clinical perspective mainlybecause of its upstream localisation which aids in early detection andlimiting metastasis and implications in the growth and metastases ofmost types of cancers. These observations suggest that c-Met kinaseinhibitors would be an effective treatment for tumors driven by c-Met,and also would prevent disseminated micrometastases from furtherprogression.

A family of novel compounds have been discovered which exhibit c-Metmodulating ability and have an ameliorating effect against disordersrelated to abnormal c-Met activity such as Johnson & Johnson'sJNJ-38877605, Amgen's AMG-458, Eisai's E-7050 and Pfizer's PF-04217903.However, to date, none of them have been used in a clinical study.

More recently Dussault et. al., Anti-Cancer Agents in MedicinalChemistry, 2009, 9(2), 221-229, have provided additional insight about areceptor tyrosine kinase namely, RON (recepteur d'origine nantais) whichis closely related to c-Met. Both c-MET and RON receptors uponactivation can induce cell migration, invasion, proliferation andsurvival. Moreover, both possess oncogenic activity in vitro and in vivoand are often dysregulated in human cancers.

While c-Met is now a well-accepted target for anti-cancer treatment,less is known about the role of RON in cancer. Despite their commonattributes, c-Met and RON are activated by different mechanisms incancer cells. Due to a significant homology between the two RTKs, somesmall molecule kinase inhibitors of c-Met have inhibitory activity onRON suggesting that both receptors might be involved in cancerprogression. The review (Dussault et al., supra) discusses the relevanceof both c-Met and RON deregulation in human cancers and the progressmade in identifying small molecule kinase inhibitors that can block theactivity of these targets in vitro and in animal models. One of thecompounds discussed in the review, AMG-458, inhibited c-Met and RON withIC₅₀s of 4 and 9 nM respectively.

Various research groups around the world such as Amgen, Arquel,AstraZeneca, Bristol-Myers Squibb, Exelixis, Eisai, Incyte, MethylGene,Pfizer, SGX Pharma, SmithKline Beecham, Schering, Vertex, Xcovery,Novartis and others have been working on targeting either single, dualor multiple kinase targets.

Patent literature belonging to some of these applicants include thefollowing patents and/or patent applications: U.S. Pat. No. 7,446,199;U.S. Pat. No. 7,470,693; U.S. Pat. No. 7,459,562; U.S. Pat. No.7,439,246; U.S. Pat. No. 7,432,373; U.S. Pat. No. 7,348,325; U.S. Pat.No. 7,173,031; U.S. Pat. No. 7,314,885; U.S. Pat. No. 7,169,800; US20100105656, US20090012076; US20080312232; US20080161305; US20070244116;US20070225307; US20070054928; US20070179130; US20070254868;US20070191369; US20060173055; US20060135537; US20050148574;US20050137201; US20050101650; WO2009002806; WO2008088881; WO2008051805;WO2008102870; WO2008078085; WO2008060866; WO200854702; WO2008036272;WO2007111904; WO2007064797; WO2006052913; WO2006021881; WO2006021886;WO2006021884; WO2006108059; WO2006014325; WO2006052913; WO200507891;WO2005030140; WO2005040345; WO2005028475; WO2005016920.

Recent PCT patent applications viz., WO2009058728, WO2009058729,WO2009058730 and WO2009058739 all assigned to Schering corporationdisclose a series of thiazole carboxamide compounds as protein kinaseinhibitors and more specifically to be inhibiting Aurora, MEK1 and/orCDK2 kinases.

Further review and literature disclosure on protein kinase moleculeshave been given by Isabelle Dussault et. al., (see; Anti-Cancer Agentsin Medicinal Chemistry, 2009, 9, 221-229), Ted L. Underiner et. al.,(see; Anti-Cancer Agents in Medicinal Chemistry, 2010, 10, 7-27) andStephen Claridge et. al (see; Bioorganic & Medicinal Chemistry Letters18 (2008) 2793-2798). All of these patents and/or patent applicationsand literature disclosures are incorporated herein as reference in theirentirety for all purposes.

Despite the advances made in the area of kinases and in particular therole that c-met, RON, EGFR or KDR pathway plays in human diseases,challenges remain in term of the complexities of the target involved,the protein structure of the kinases, specificity issues for variouskinase inhibitors, side effects and desired clinical benefits expectedform the small molecule inhibitors. Accordingly, there still remains anunmet and dire need for small molecule compounds having specificitytowards either one, two or multiple kinase inhibitors in order toregulate and/or modulate transduction of kinases, particularly c-Met,RON, EGFR or KDR for the treatment of diseases and disorders associatedwith kinases-mediated events.

The c-Met pathway plays an important role in the above described humandiseases including cancer. There are no c-Met inhibitors or antagoniststhat are currently available for treating these human disorders that arecharacterized by abnormal HGF/c-Met signaling. Therefore, there is aclear unmet medical need for compounds which inhibit c-Met and otherkinases. The compounds, compositions, and pharmaceutical methodsprovided herein help meet this need.

SUMMARY OF THE INVENTION

The present invention is directed to compounds useful as protein kinasemodulators and in particular as inhibitors of c-Met.

In one embodiment, the compound of the present invention has the formulaI:

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinX is CR¹ or N;Cy¹ and Cy² may be same or different and are independently selected fromsubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclic group, substituted or unsubstituted aryl, and substitutedor unsubstituted heteroaryl;L₁ is absent or selected from —O—, —S(═O)_(q)—, —NR^(a)—,—(CR^(a)R^(b))_(n)—, —C(═Y)—, —C(═Y)—C(═Y)—,—CR^(a)R^(b)—C(═Y)—CR^(a)R^(b)—, —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)R^(b)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)R^(b)—S(═O)_(q)—NR^(a)R^(b)—,—NR^(a)R^(b)—NR^(a)R^(b)—, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, and substituted orunsubstituted heterocyclyl;L₂ is selected from —O—, —S(═O)_(q)—, —NR^(a)—, —(CR^(a)R^(b))_(n)—,—C(═Y)—, —C(═Y)—C(═Y)—, —CR^(a)R^(b)—C(═Y)—CR^(a)R^(b)—,—CR^(a)R^(b)—Y—CR^(a)R^(b)—, —C(═Y)—NR^(a)R^(b)—,—NR^(a)R^(b)—C(═Y)—NR^(a)R^(b)—, —S(═O)_(q)—NR^(a)R^(b)—,—NR^(a)R^(b)—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)R^(b)—NR^(a)R^(b)—,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl;each occurrence of R¹ and R² may be same or different and isindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,—OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), —C(═Y)—R^(a),—CR^(a)R^(b)—C(═Y)—R^(a), —CR^(a)R^(b)—Y—CR^(a)R^(b)—,—C(═Y)—NR^(a)R^(b)—, —NR^(a)R^(b)—C(═Y)—NR^(a)R^(b)—,—S(═O)_(q)—NR^(a)R^(b)—, —NR^(a)R^(b)—S(═O)_(q)—NR^(a)R^(b)—,—NR^(a)R^(b)—NR^(a)R^(b)—, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substitutedor unsubstituted C₃₋₆ cycloalkylalkyl, and substituted or unsubstitutedC₃₋₆ cycloalkenyl;each occurrence of R^(a) and R^(b) may be same or different and areindependently selected from hydrogen, nitro, hydroxy, cyano, halogen,substituted or unsubstituted C₁₋₆ alkyl, substituted or unsubstitutedC₂₋₆ alkenyl, substituted or unsubstituted C₂₋₆ alkynyl, substituted orunsubstituted C₃₋₆ cycloalkyl, substituted or unsubstituted C₃₋₆cycloalkylalkyl, and substituted or unsubstituted C₃₋₆ cycloalkenyl, orwhen two R^(a) and/or R^(b) substituents are directly bound to a commonatom, they may be joined to form a substituted or unsubstituted,saturated or unsaturated 3-10 member ring, which may optionally includeone or more heteroatoms which may be same or different and are selectedfrom O, NR^(c) or S;each occurrence of R^(c) is independently selected from hydrogen, nitro,hydroxy, cyano, halogen, substituted or unsubstituted C₁₋₆ alkyl,substituted or unsubstituted C₂₋₆ alkenyl, substituted or unsubstitutedC₂₋₆ alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl, substitutedor unsubstituted C₃₋₆ cycloalkylalkyl, and substituted or unsubstitutedC₃₋₆ cycloalkenyl;each occurrence of Y is independently selected from O, S, and NR^(a);each occurrence of n independently represents 0, 1, 2, 3 or 4; and eachoccurrence of q independently represents 0, 1 or 2.

Another embodiment is a compound of formula (IA):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereineach occurrence of R² is independently hydrogen, nitro, hydroxy, cyano,halogen, —OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), —C(═O)—R^(a), or—C(═O)—R^(a), wherein R^(a) and R^(b) in the R² group are independentlyhydrogen, hydroxy, or substituted or unsubstituted C₁₋₆ alkyl;and all the other variables are the same as described above for compoundof formula (I).

Further preferred is a compound of formula (I) and (IA) wherein Cy¹ isselected from: (The squiggly lines (

) in the structures below represent the point of attachment of thestructure to the rest of the compound.)

Yet another embodiment is a compound of formula (IA-I):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinD is substituted or unsubstituted monocyclic aryl or substituted orunsubstituted monocyclic heteroaryl;each occurrence of R² is independently hydrogen, nitro, hydroxy, cyano,halogen, —OR^(a), —S(═O)_(q)—R^(a), —NR^(a)R^(b), —C(═O)—R^(a),—C(═O)—R^(a), wherein each occurrence of R^(a) and R^(b) in group R² isindependently hydrogen, hydroxy, or substituted or unsubstituted C₁₋₆alkyl;and all other variables are the same as described herein above.

Further preferred is a compound of formula (IA-1) wherein L₂ is—CR^(a)R^(b).

Further preferred is a compound of formula (IA-1) wherein D issubstituted with one to five substituents selected from halogen,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,—COR^(x), —CONR^(x)R^(y), —S(O)_(q)NR^(x)R^(y) or —NR^(x)R^(y);

wherein each occurrence of R^(x) and R^(y) is independently selectedfrom hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocycyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(z), —C(O)R^(z),—C(S)R^(z), —C(O)NR^(z)R^(z), —C(O)ONR^(z)R^(z), —NR^(z)R^(z),—NR^(z)CONR^(z)R^(z), —N(R^(z))SOR^(z), —N(R^(z))SO₂R^(z),—(═N—N(R^(z))R^(z)), —NR^(z)C(O)OR^(z), —NR^(z)C(O)R^(z)—,—NR^(x)C(S)R^(y)—NR^(z)C(S)NR^(z)R^(z), —SONR^(z)R^(z)—,—SO₂NR^(z)R^(z)—, —OR^(z), —OR^(z)C(O)NR^(z)R^(z), —OR^(z)C(O)OR^(z)—,—OC(O)R^(z), —OC(O)NR^(z)R^(z), —R^(z)NR^(z)C(O)R^(z), —R^(z)OR^(z),—R^(z)C(O)OR^(z), —R^(z)C(O)NR^(z)R^(z), —R^(z)C(O)R^(z),—R^(z)OC(O)R^(z), —SR^(z), —SOR^(z), —SO₂R^(z), and —ONO₂, or any two ofR^(x) and R^(y) which are directly bound to a common atom may be joinedto form (i) a substituted or unsubstituted, saturated or unsaturated3-14 membered ring, which may optionally include one or more heteroatomswhich may be the same or different and are selected from O, NR^(z) or S,or (ii) an oxo (═O), thio (═S) or imino (═NR^(z)), whereineach occurrence of R^(z) is independently hydrogen, hydroxy, halogen,carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocycyl, substituted or unsubstituted heterocyclcyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, and —ONO₂, or any two of R^(z) which are directly boundto a common atom may be joined to form (i) a substituted orunsubstituted, saturated or unsaturated 3-14 membered ring, which mayoptionally include one or more heteroatoms which may be the same ordifferent and are selected from O, NR′ (where R′ is H or alkyl) or S, or(ii) an oxo (═O), thio (═S) or imino (═NR^(z)); andq in the group D is 0, 1 or 2.

Further preferred is a compound of formula (IA-1) wherein D is selectedfrom

Yet another embodiment is a compound of formula (II)

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinA is selected from halogen, —OR^(c), —S(═O)_(q)—R^(c), —NR^(c)R^(d),—(CR^(c)R^(d))_(n)—R^(e), —C(═Y)—R^(c), —C(═Y)—C(═Y)—R^(c),—CR^(c)R^(d)—C(═Y)—CR^(c)R^(d)—R^(e), —CR^(c)R^(d)—Y—CR^(c)R^(d)—R^(e),—C(═Y)—NR^(c)R^(d), —NR^(c)—C(═Y)—NR^(c)R^(d), —S(═O)_(q)—NR^(c)R^(d),—NR^(c)—S(═O)_(q)—NR^(c)R^(d), —NR^(c)—NR^(c)R^(d), substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl,and substituted or unsubstituted C₃₋₆ cycloalkenyl; or when two R^(c)and R^(d) substituents are directly bound to a common atom, they may bejoined to form a substituted or unsubstituted, saturated or unsaturated3-10 member ring, which may optionally include one or more heteroatomswhich may be same or different and are selected from O, NR^(e) or S;each occurrence of R^(c), R^(d), and R^(e) are independently selectedfrom hydrogen, hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkenylalkyl, substituted or unsubstituted heterocyclic ring,substituted or unsubstituted heterocycylalkyl ring, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted guanidine, —COOR^(x),—C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y),—NR^(y)R^(z), —NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y),—(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)R^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y), —NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, wherein eachoccurrence of R^(x), R^(y) and R^(z) in each of the above groups isindependently hydrogen, substituted or unsubstituted amino, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substitutedor unsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocyclic ring, substituted or unsubstituted heterocyclylalkyl ring,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, and substituted orunsubstituted heteroarylalkyl, or any two of R^(x), R^(y) and R^(z)which are directly bound to a common atom may be joined to form (i) anoxo (C═O), thio (C═S) or imino (C═NR′) group (where R′ is H or alkyl) or(ii) substituted or unsubstituted, saturated or unsaturated 3-10membered ring, which may optionally include one or more heteroatomswhich may be the same or different and are selected from O, NR′ (whereR′ is H or alkyl) or S; andall other variables are the same as described above for compound offormula (I).

Yet another embodiment is a compound of formula (IIA):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinR^(c) and R^(d) together with the nitrogen to which they are attachedform a substituted or unsubstituted, saturated or unsaturated 3-10member ring, which may optionally include one or more heteroatoms whichmay be same or different and are selected from O, NR^(e) or S; andall other variables are the same as described above for compound offormula (II).

Further preferred is a compound of formula (IIA) wherein NR^(c)R^(d) isselected from

wherein each occurrence of R^(x) and R^(y) is independently selectedfrom hydrogen, substituted or unsubstituted alkyl, and substituted orunsubstituted alkoxy, or any two of R^(x) and R^(y) which are directlybound to a common atom may be joined to form an oxo (C═O), thio (C═S) orimino (C═NR′) group (where R′ is H or alkyl) or, any two of R^(x) andR^(y) may be joined to form a substituted or unsubstituted, saturated orunsaturated 3-6 membered ring, which may optionally include one or moreheteroatoms which may be the same or different and are selected from O,NR′ (where R′ is H or alkyl) or S.

Further preferred is a compound of formula (IIA) wherein NR^(c)R^(d) isselected from

Yet another embodiment is a compound of formula (III):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinU and V are each independently selected from CR³ or N;W is selected from O, S, or NR⁴;each occurrence of R³ is independently hydrogen, halogen, cyano (CN),—OR^(c), —S(═O)_(q)—R^(c), —NR^(c)R^(d), substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl,substituted or unsubstituted C₃₋₆ cycloalkylalkyl, or substituted orunsubstituted C₃₋₆ cycloalkenyl;R⁴ is selected from hydrogen, hydroxy, carboxyl, cyano, oxo (═O), thio(═S), substituted or unsubstituted alkyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted C₃₋₆ cycloalkyl,substituted or unsubstituted C₃₋₆ cycloalkylalkyl, and substituted orunsubstituted C₃₋₆ cycloalkenyl;R⁵ is selected from hydrogen, hydroxy, halogen, carboxyl, cyano, nitro,oxo (═O), thio (═S), substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstituted heterocyclicring, substituted or unsubstituted heterocyclylalkyl, substituted orunsubstituted aryl, substituted or unsubstituted arylalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, substituted or unsubstituted guanidine, —COOR^(x),—C(O)R^(x), —C(S)R^(x), —C(O)NR^(x)R^(y), —C(O)ONR^(x)R^(y),—NR^(x)R^(z), —NR^(x)CONR^(y)R^(z), —N(R^(x))SOR^(y), —N(R^(x))SO₂R^(y),—(═N—N(R^(x))R^(y)), —NR^(x)C(O)OR^(y), —NR^(x)C(O)R^(y)—,—NR^(x)C(S)R^(y), —NR^(x)C(S)NR^(y)R^(z), —SONR^(x)R^(y)—,—SO₂NR^(x)R^(y)—, —OR^(x), —OR^(x)C(O)NR^(y)R^(z), —OR^(x)C(O)OR^(y)—,—OC(O)R^(x), —OC(O)NR^(x)R^(y), —R^(x)NR^(y)C(O)R^(z), —R^(x)OR^(y),—R^(x)C(O)OR^(y), —R^(x)C(O)NR^(y)R^(z), —R^(x)C(O)R^(x),—R^(x)OC(O)R^(y), —SR^(x), —SOR^(x), —SO₂R^(x), and —ONO₂, whereinR^(x), R^(y) and R^(z) in each of the above groups can be hydrogen,substituted or unsubstituted amino, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl,substituted or unsubstituted cycloalkenyl, substituted or unsubstitutedheterocyclic ring, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedarylalkyl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heteroarylalkyl, or any two of R^(x), R^(y) and R^(z)which are directly bound to a common atom may be joined to form an oxo(C═O), thio (C═S) or imino (C═NR′) group (where R′ is H or alkyl) orsubstituted or unsubstituted, saturated or unsaturated 3-10 memberedring, which may optionally include one or more heteroatoms which may bethe same or different and are selected from O, NR′ (where R′ is H oralkyl) or S;or when W is NR⁴, R⁴ and R⁵ together with the nitrogen to which they areattached form a substituted or unsubstituted, saturated or unsaturated3-10 member ring, which may optionally include one or more heteroatomswhich may be same or different and are selected from O, NR^(e) or S; andall the other variables are the same as described above for compound offormula (I).

Further preferred is a compound of formula (III) wherein U is CR³.

Further preferred is a compound of formula (III) wherein V is N.

Further preferred is a compound of formula (III) wherein W is O or NR⁴.

Further preferred is a compound of formula (III) wherein —U═V—W—R⁵ is

Yet another embodiment is compound of formula (IIIA) or (IIIB):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, wherein all the variables are the same as described above forcompound of formula (III).

Further preferred is a compound of formula (IIIA) wherein —CR³═N—O—R⁵ isselected from

Further preferred is a compound of formula (IIIA) wherein —CR³═N—NR⁴R⁵is selected from

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein X is CR¹.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein X is N.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein R¹ is H.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein each of R² is H;

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein L₂ is —CR^(a)CR^(b)—.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein L₂ is —CH₂—, —CH(OH)—, —CHF—,—CF₂—, —CH(CH₃)— or —C(CH₃)₂—.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein L₂ is —CH₂— or —CH(CH₃)—.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein Cy² is substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl.

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IIA), (III), (IIIA) or (IIIB) wherein Cy² is selected from

Further preferred is a compound of formula (I), (IA), (IA-1), (II),(IA), (III), (III) or (IIB) wherein Cy² is selected from

Yet another embodiment is a compound of formula (IV):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinB is selected from L₁-Cy₁, Cy₁, D, A, NR^(c)R^(d) and —U═V—W—R⁵ (e.g.,Cy¹, D, NR^(c)R^(d) or —U═V—W—R⁵);R^(a) and R^(b), located between the two bicyclic groups, areindependently selected from hydrogen, halogen, and substituted orunsubstituted (C₁₋₆) alkyl, or both together with the carbon atom towhich they are attached form a saturated 3 to 6 member cyclic ring whichmay optionally include one or more heteroatoms which may be same ordifferent and are selected from O, NR^(e) and S;Z is selected from CR^(c), S, O, NR^(c), R^(c)C═CR^(c), —N═CR^(c)—, and—R^(c)C═N—;Z₁ is selected from N, NR^(c) and CR^(c);R^(c) is absent or selected from hydrogen, hydroxy and halogen;and all other variables are the same as described herein above.

Further preferred is a compound of formula (IV) wherein X is N.

Further preferred is a compound of formula (IV) wherein each occurrenceof R² is H.

Further preferred is a compound of formula (IV) wherein each of R^(a)and R^(b) is hydrogen.

Further preferred is a compound of formula (IV) wherein R^(a) methyl andR^(b) is hydrogen.

Further preferred is a compound of formula (IV) wherein R^(a) is fluoroand R^(b) is hydrogen.

Further preferred is a compound of formula (IV) wherein R^(a) and R^(b)both are fluoro.

Further preferred is a compound of formula (IV) wherein R^(a) and R^(b)both are methyl.

Further preferred is a compound of formula (IV) wherein Z is CR^(c), N,S, O, HC═CH—, or —N═CH—.

Further preferred is a compound of formula (IV) wherein Z₁ is CH or N.

Further preferred is a compound of formula (IV) wherein Z is —HC═CH—,—S— or —O— and Z₁ is CH.

Further preferred is a compound of formula (IV) wherein Z is —HC═CH— andZ₁ is CH.

Further preferred is a compound of formula (IV) wherein Z is —S— and Z₁is CH.

Further preferred is a compound of formula (IV) wherein Z is —O— and Z₁is CH.

Further preferred is a compound of formula (IV) wherein Z is —CH— and Z₁is NH.

Further preferred is a compound of formula (IV), wherein each occurrenceof R^(c) is hydrogen or fluoro.

Further preferred is a compound of formula (IV) wherein B is L₁-Cy¹,wherein L₁-Cy¹ is as described above for the compound of formula (I).

Further preferred is a compound of formula (IV) wherein B is Cy¹,wherein Cy¹ is as described above for the compound of formula (IA).

Further preferred is a compound of formula (IV) wherein D is asdescribed above for the compound of formula (IA-1).

Further preferred is a compound of formula (IV) wherein A is asdescribed above for the compound of formula (II).

Further preferred is a compound of formula (IV) wherein B isNR^(c)R^(d), wherein NR^(c)R^(d) is as described above for the compoundof formula (IIA).

Further preferred is a compound of formula (IV) wherein B is —U═V—W—R⁵,wherein U═V—W—R⁵ is as described above for the compound of formula(III).

Further preferred is a compound of formula (IV) wherein U═V—W—R⁵ is—CR³═N—O—R⁵, wherein —CR³═N—O—R⁵ is as described above for the compoundof formula (IIIA).

Further preferred is a compound of formula (IV) wherein U═V—W—R⁵ is—CR³═N—NR⁴R⁵, wherein —CR³═N—NR⁴R⁵ is as described above for thecompound of formula (IIIB).

In one embodiment, in the compound of formula (IV), (a) the bicyclicring containing ring atoms Z and Z₁ is quinoline, benzo[d]thiazol-6-yl,or an N-oxide thereof, which is optionally substituted with one or twohalogen (e.g., F), (b) R^(a), R^(b), and each R^(c) are hydrogen, (c)each R² is hydrogen, and (d) B is substituted phenyl, substitutedthiophenyl, —CR³═N—O—R⁵ or —CR³═N—NR⁴R⁵ (where R³, R⁴, and R⁵ are asdescribed above for the compounds of formulas (IIIA) and (IIIB)). Forexample, B may be 4-amidophenyl (i.e., 4-NH₂C(O)-Ph) or4-(R′—NHC(O))-phenyl (where R′ is (C₁-C₄) alkyl), where the phenyl groupmay optionally be further substituted by one, two, or three substituentsselected from halogens (e.g., F or Cl) and fluorinated methyl (e.g.,—CF₃). In another embodiment, B is thiophenyl substituted withhydroxymethyl, or B is a pyrazolyl group optionally substituted with(C₁-C₆) alkyl or hydroxy (C₁-C₆) alkyl.

Yet another embodiment is a compound of formula (IVA) or (IVB):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt (e.g.,pharmaceutically acceptable salt), prodrug (e.g., ester), or N-oxidethereof, whereinR^(a) is halogen or substituted or unsubstituted (C₁₋₆) alkyl (e.g.,methyl);and all other variables are the same as described herein above.

In one embodiment, the bicyclic ring containing ring atoms Z and Z₁ inthe compound of formula (IVA) is quinoline or an N-oxide thereof, whichis optionally substituted with one or two halogen (e.g., F).

In one embodiment, the bicyclic ring containing ring atoms Z and Z₁ inthe compound of formula (IVB) is quinoline or an N-oxide thereof, whichis optionally substituted with one or two halogen (e.g., F).

In one embodiment, the bicyclic ring containing ring atoms Z and Z₁ inthe compound of formula (IVA) is benzo[d]thiazol-6-yl or an N-oxidethereof, which is optionally substituted with one or two halogen (e.g.,F).

In one embodiment, the bicyclic ring containing ring atoms Z and Z₁ inthe compound of formula (IVB) is benzo[d]thiazol-6-yl or an N-oxidethereof, which is optionally substituted with one or two halogen (e.g.,F).

In a preferred embodiment, B in compound (IVA) or (IVB) is substitutedphenyl, substituted thiophenyl, —CR³═N—O—R⁵ or —CR³═N—NR⁴R⁵ (where R³,R⁴, and R⁵ are as described above for the compounds of formulas (IIIA)and (IIIB)). For example, B may be 4-amidophenyl (i.e.,4-NH₂C(O)-phenyl) or 4-(R′—NHC(O))-phenyl (where R′ is (C₁-C₄) alkyl),where the phenyl group may optionally be further substituted by one,two, or three substituents selected from halogens (e.g., F or Cl) andfluorinated methyl (e.g., —CF₃). In another embodiment, B is thiophenylsubstituted with hydroxymethyl, or B is a pyrazolyl group optionallysubstituted with (C₁-C₆) alkyl or hydroxy (C₁-C₆) alkyl.

In a preferred embodiment, each R² is hydrogen.

Representative compounds of the present invention include thosespecified below and pharmaceutically acceptable salts thereof. Thepresent invention should not be construed to be limited to them.

-   1.    6-((5-(4-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   2.    6-((5-(3-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   3.    3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde-   4.    (3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol-   5.    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde-   6.    (4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol-   7. Methyl    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate-   8.    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic    acid-   9.    N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   10.    4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde-   11.    (4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol-   12. Methyl    2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoate-   13.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic    acid-   14.    2-Fluoro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   15.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   16.    (2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)    methanol-   17. Methyl    4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluoro    benzoate-   18.    4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluoro    benzoic acid-   19.    4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluoro-N-methyl    benzamide-   20.    N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   21.    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   22. Lithium    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate-   23.    6-((5-(3-(trifluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   24.    3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol-   25.    6-((5-(3-(difluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   26.    (4-Methylpiperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone-   27.    N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   28.    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide-   29. tert-Butyl    4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamido)piperidine-1-carboxylate-   30.    N-(Piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   31.    N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]    pyridin-5-yl)benzamide-   32.    (S)-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo    [4,5-b]pyridin-5-yl)phenyl)methanone hydrochloride-   33.    (4-(2-hydroxyethyl)piperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]    pyridin-5-yl)phenyl)methanone-   34.    (R)-(3-hydroxypyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone    hydrochloride-   35.    N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   36.    N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   37.    N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   38.    (4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]    pyridin-5-yl)phenyl)methanone-   39.    N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   40.    N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    hydrochloride-   41.    (2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    phenyl)methanol hydrochloride-   42.    6-((5-(3-Fluoro-4-(methoxymethyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   43.    N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   44.    2-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]    pyridin-5-yl)benzamide-   45.    N-cyclohexyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   46.    N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   47.    2-Fluoro-N-(pyridin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   48.    N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   49.    2-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   50. Methyl    2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamido)acetate.-   51.    2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamido)acetic acid-   52.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide-   53. Methyl    3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate-   54.    3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic    acid-   55.    N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   56.    6-((5-(3-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   57. Methyl    3-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    phenyl amino) propanoate-   58.    3-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    phenylamino)propanoic acid-   59.    2-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    hydrochloride-   60.    N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   61.    N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   62.    2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   63.    N-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)    acetamide-   64.    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline-   65.    6-((5-(3,4-Dimethoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   66.    6-((5-(3-Fluoro-4-methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   67.    6-((5-(4-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   68.    6-((5-(2-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   69.    N-(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)    acetamide-   70.    6-((5-(3-(2,2,2-Trifluoroethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   71.    3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline-   72.    N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   73.    N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   74.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    hydrochloride-   75.    6-((5-(3-Fluoro-4-isopropoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   76.    N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   77.    N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   78.    2-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   79.    6-((5-(4-(Cyclopropylmethoxy)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline-   80.    6-((5-(3-Fluoro-4-isobutoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   81.    3-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    phenoxy)-N,N-dimethylpropan-1-amine-   82. Methyl    2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoate-   83.    2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoic acid-   84.    2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   85.    6-((5-(3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   86.    6-((5-(3-Fluoro-4-(2-methoxyethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   87.    2-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   88.    6-((5-(4-(Cyclopropylcarbamoyl)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline 1-oxide-   89.    N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   90.    N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   91.    N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   92.    2-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   93.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide-   94.    2-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   95.    N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzenesulfonamide-   96.    N,N-Dimethyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    aniline-   97.    2-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   98.    N-Cyclopentyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   99.    2-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   100. Methyl    2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoate-   101.    2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic    acid-   102.    2-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   103.    2-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   104.    N-Cyclobutyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]    pyridin-5-yl)benzamide-   105.    2-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   106.    N-Cyclopropyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo    [4,5-b] pyridin-5-yl)benzamide-   107.    N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   108.    2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide:-   109.    2-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   110.    2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   111.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(thiazol-2-yl)benzamide-   112.    N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   113.    2-Chloro-N-cyclopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   114.    2-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   115.    2-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   116.    N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   117.    2-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   118.    1-Ethyl-3-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    phenyl) urea-   119.    2-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   120.    2-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   121.    N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    dihydrochloride-   122.    2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide-   123.    2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   124.    2-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   125.    N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    dihydrochloride-   126.    2-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    dihydrochloride-   127.    2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide    hydrochloride-   128. Methyl    2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoate-   129.    2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoic acid-   130.    2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   131. Methyl    2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate-   132.    2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoic acid-   133.    2-Chloro-N-ethyl-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   134.    2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   135. Methyl    2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate-   136.    2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoic acid-   137.    2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   138.    3-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   139.    2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide    hydrochloride-   140.    2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   141.    2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   142.    2-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   143.    6-((5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   144.    6-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   145.    6-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   146.    2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)    ethanol-   147.    6-((5-(1H-Pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline-   148.    6-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline-   149.    6-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-imidazo    [4,5-b]pyridin-3-yl)methyl)quinoline-   150.    2-(4-(3-(Quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)    ethanol-   151.    2-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-ylamino)ethanol-   152.    6-((5-(1H-Imidazol-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   153.    6-((5-(1-Propyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   154. Ethyl    2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)acetate-   155.    2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)    acetic acid-   156. tert-Butyl    4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate-   157.    6-((5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline-   158.    (R)-1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol-   159.    3-(4-Fluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-   160.    3-(4-Fluorobenzyl)-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-   161.    2-(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)    ethanol-   162.    6-(1-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline-   163.    6-(1-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline-   164.    2-(4-(3-(1-(Quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol-   165.    2-(4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol-   166. tert-Butyl    4-(4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate-   167.    3-(2-Chloro-3,6-difluorobenzyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine    hydrochloride-   168.    6-((5-(3-Methyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   169.    6-((5-(1H-Indol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   170.    6-((5-(1H-Indol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   171.    6-((5-(2-Chloropyridin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   172.    6-((5-(3-Methyl-1H-indazol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   173.    6-((5-(Pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   174.    (S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   175.    (S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline hydrochloride-   176.    4-(2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethyl)morpholine    hydrochloride-   177.    6-((5-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   178.    6-((5-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline 1-oxide-   179.    6-((5-(1,3-Dimethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline-   180.    5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrimidin-2-amine-   181. tert-Butyl    3-ethyl-6-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-indazole-1-carboxylate-   182.    4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophene-2-carbaldehyde-   183.    6-((5-(2-Methoxypyrimidin-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   184.    6-((5-(Benzo[d][1,3]dioxol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   185.    6-((5-(2,3-Dihydrobenzofuran-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   186.    5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridin-2-amine-   187.    6-((5-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline-   188.    (4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophen-2-yl)    methanol-   189.    6-(2-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo    [4,5-b] pyridin-3-yl)propan-2-yl)quinoline-   190.    2-(4-(3-(2-(Quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol-   191.    6-((5-(3-ethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   192.    6-(2-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)    quinoline-   193.    6-((5-(4-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   194.    6-((5-(5-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   195.    4-(5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridin-2-yl)    morpholine-   196.    6-((5-(6-(Piperidin-1-yl)pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline-   197.    6-((5-(1-Ethyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   198.    6-((5-(1-Isopropyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline-   199.    6-((5-(1-Isobutyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   200.    1-(Pyrrolidin-1-yl)-2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanone-   201.    6-((5-(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl)quinoline-   202.    N-Phenyl-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine-   203.    6-((5-Phenoxy-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline-   204. Methyl    2-fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzoate-   205.    2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoic    acid-   206.    2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   207.    2-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   208.    1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone-   209.    2-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)    hydrazinecarboxamide-   210.    4-(3-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-chloro    benzamide-   211.    2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    phenyl)propan-2-ol-   212.    2-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide-   213.    3-(2-Chloro-3,6-difluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine-   214.    (±)2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   215.    2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzamide-   216.    1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone    oxime-   217.    1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanoneO-methyl    oxime-   218.    N′-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)    acetohydrazide-   219.    6-((5-(4-Methylpiperazin-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)    quinoline-   220.    N′-(1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)    isonicotinohydrazide-   221. (−)    2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   222. (+)    2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide-   223.    4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trifluoromethyl)benzamide-   224.    6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline 1-oxide-   225.    2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)    benzamide hydrochloride-   226.    6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)    methyl) quinoline 1-oxide-   227.    6-((5-(3-methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

TABLE 1 Compound Structure Ex 1

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Ex 51

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Ex 110

Ex 111

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Ex 114

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Yet another embodiment of the present invention is a method for treatinga proliferative disease via modulation of a protein kinase (such asc-Met) by administering to a patient in need of such treatment aneffective amount of at least one compound of formula (I), (I-A), (IA-1),(II), (II-A), (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) as definedabove.

Yet another embodiment of the present invention is a method for treatinga proliferative disease via modulation of a protein kinase (such asc-Met) by administering to a patient in need of such treatment aneffective amount of at least one compound of formula (I), (I-A), (IA-1),(II), (II-A), (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) as definedabove, in combination (simultaneously or sequentially) with at least oneother anti-cancer agent. In a preferred embodiment, the proliferativedisease is cancer.

More particularly, the compounds of formula (I), (I-A), (IA-1), (II),(II-A), (III), (IIIA), (IIIB), (IV), (IVA) or (IVB) and pharmaceuticallyacceptable esters or salts thereof can be administered for thetreatment, prevention and/or amelioration of c-Met, RON, EGFR or KDRkinase associated diseases or disorders, including but not limited to,cancer and other proliferative diseases or disorders.

The compounds of formula (I), (I-A), (IA-1), (II), (II-A), (III),(IIIA), (IIIB), (IV), (IVA) or (IVB) are useful in the treatment of avariety of cancers, including, but not limited to, the following:

-   -   carcinoma, including that of the bladder, breast, colon, kidney,        liver, lung, including small cell lung cancer, esophagus, gall        bladder, ovary, pancreas, stomach, cervix, thyroid, prostate,        and skin, including squamous cell carcinoma;    -   hematopoietic tumors of lymphoid lineage, including leukemia,        acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell        lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins        lymphoma, hairy cell lymphoma and Burkett's lymphoma;    -   hematopoietic tumors of myeloid lineage, including acute and        chronic myelogenous leukemias, myelodysplastic syndrome and        promyelocytic leukemia;    -   tumors of mesenchymal origin, including fibrosarcoma and        rhabdomyosarcoma;    -   tumors of the central and peripheral nervous system, including        astrocytoma, neuroblastoma, glioma and schwannomas; and    -   other tumors, including melanoma, seminoma, teratocarcinoma,        osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid        follicular cancer and Kaposi's sarcoma.

Due to the key role of protein kinases in the regulation of cellularproliferation in general, inhibitors could act as reversible cytostaticagents which may be useful in the treatment of any disease process whichfeatures abnormal cellular proliferation, e.g., benign prostatichyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,atherosclerosis, pulmonary fibrosis, arthritis, psoriasis,glomerulonephritis, restenosis following angioplasty or vascularsurgery, hypertrophic scar formation, inflammatory bowel disease,transplantation rejection, endotoxic shock, and fungal infections.

The compounds of the present invention as modulators of apoptosis, areuseful in the treatment of cancer (including but not limited to thosetypes mentioned herein above), viral infections (including but notlimited to herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus andadenovirus), prevention of AIDS development in HIV-infected individuals,autoimmune diseases (including but not limited to systemic lupus,erythematosus, autoimmune mediated glomerulonephritis, rheumatoidarthritis, psoriasis, inflammatory bowel disease, and autoimmunediabetes mellitus), neurodegenerative disorders (including but notlimited to Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinalmuscular atrophy and cerebellar degeneration), myelodysplasticsyndromes, aplastic anemia, ischemic injury associated with myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, hematological diseases(including but not limited to chronic anemia and aplastic anemia),degenerative diseases of the musculoskeletal system (including but notlimited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis,cystic fibrosis, multiple sclerosis, kidney diseases and cancer pain.

The compounds of present invention can modulate the level of cellularRNA and DNA synthesis. These agents are therefore useful in thetreatment of viral infections (including but not limited to HIV, humanpapilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbisvirus and adenovirus).

The compounds of the present invention are useful in the chemopreventionof cancer. Chemoprevention is defined as inhibiting the development ofinvasive cancer by either blocking the initiating mutagenic event or byblocking the progression of pre-malignant cells that have alreadysuffered an insult or inhibiting tumor relapse. The compounds are alsouseful in inhibiting tumor angiogenesis and metastasis. One embodimentof the invention is a method of inhibiting tumor angiogenesis ormetastasis in a patient in need thereof by administering an effectiveamount of one or more compounds of the present invention.

Another embodiment of the present invention is a method of treating animmune system-related disease (e.g., an autoimmune disease), a diseaseor disorder involving inflammation (e.g., asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, inflammatory bowel disease,glomerulonephritis, neuroinflammatory diseases, multiple sclerosis,uveitis and disorders of the immune system), cancer or otherproliferative disease, a hepatic disease or disorder, a renal disease ordisorder. The method includes administering an effective amount of oneor more compounds of the present invention.

Examples of immune disorders include psoriasis, rheumatoid arthritis,vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis,asthma, inflammatory muscle disease, allergic rhinitis, vaginitis,interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic orxenogeneic transplantation (organ, bone marrow, stem cells and othercells and tissues) graft rejection, graft-versus-host disease, lupuserythematosus, inflammatory disease, type I diabetes, pulmonaryfibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g.,Hashimoto's and autoimmune thyroiditis), myasthenia gravis, autoimmunehemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsinghepatitis, primary biliary cirrhosis, allergic conjunctivitis and atopicdermatitis.

In one embodiment, the compounds described herein are used asimmunosuppresants to prevent transplant graft rejections, allogeneic orxenogeneic transplantation rejection (organ, bone marrow, stem cells,other cells and tissues), and graft—versus—host disease. In otherembodiments, transplant graft rejections result from tissue or organtransplants. In further embodiments, graft-versus-host disease resultsfrom bone marrow or stem cell transplantation. One embodiment is amethod of preventing or decreasing the risk of transplant graftrejection, allogeneic or xenogeneic transplantation rejection (organ,bone marrow, stem cells, other cells and tissues), or graft—versus—hostdisease by administering an effective amount of one or more compounds ofthe present invention.

The compounds of the present invention are also useful in combination(administered together or sequentially) with known anti-cancertreatments such as radiation therapy or with cytostatic or cytotoxic oranticancer agents, such as for example, but not limited to, DNAinteractive agents, such as cisplatin or doxorubicin; topoisomerase IIinhibitors, such as etoposide; topoisomerase I inhibitors such as CPT-11or topotecan; tubulin interacting agents, such as paclitaxel, docetaxelor the epothilones (for example ixabepilone), either naturally occurringor synthetic; hormonal agents, such as tamoxifen; thymidilate synthaseinhibitors, such as 5-fluorouracil; and anti-metabolites, such asmethotrexate, other tyrosine kinase inhibitors such as Iressa andOSI-774; angiogenesis inhibitors; EGF inhibitors; VEGF inhibitors; CDKinhibitors; SRC inhibitors; c-Kit inhibitors; Her1/2 inhibitors andmonoclonal antibodies directed against growth factor receptors such aserbitux (EGF) and herceptin (Her2) and other protein kinase modulatorsas well.

The compounds of the present invention are also useful in combination(administered together or sequentially) with one or more steroidalanti-inflammatory drugs, non-steroidal anti-inflammatory drugs (NSAIDs)or Immune Selective Anti-Inflammatory Derivatives (ImSAIDs).

The invention further provides a pharmaceutical composition comprisingone or more compounds of the present invention (such as a compoundhaving formula (I), (I-A), (IA-1), (II), (II-A), (III), (IIIA), (IIIB),(IV), (IVA) or (IVB)) together with a pharmaceutically acceptablecarrier. The pharmaceutical composition may further comprise one or moreof the active ingredients identified above, such as other anti-canceragents. In one embodiment, the pharmaceutical composition includes atherapeutically effective amount of one or more compounds of formula(I), (I-A), (IA-1), (II), (II-A), (III), (IIIA), (IIIB), (IV), (IVA) or(IVB).

Yet another embodiment is a method of treating leukemia in a patient inneed thereof by administering a therapeutically effective amount of acompound of the present invention. For example, the compounds of thepresent invention are effective for treating carcinoma of the bladder,carcinoma of the breast, carcinoma of the colon, carcinoma of thekidney, carcinoma of the liver, carcinoma of the lung, small cell lungcancer, esophageal cancer, gall bladder cancer, ovarian cancer,pancreatic cancer, stomach cancer, cervical cancer, thyroid cancer,prostate cancer, skin cancer, squamous cell carcinoma;cholangiocarcinoma cancer, tumors of mesenchymal origin, fibrosarcoma,rhabdomyosarcoma; tumors of the central and peripheral nervous system,astrocytoma, neuroblastoma, glioma, schwannoma; melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma, synovial sarcoma,rhabdomyosarcoma, MFH/fibrosarcoma, leiomyosarcoma, multiple myeloma,lymphoma, glioblastoma, astrocytoma, melanoma, mesothelioma, Wilm'stumor, hematopoietic tumors of lymphoid lineage, leukemia, acutelymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma,T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkins lymphoma, hairy celllymphoma and Burkett's lymphoma; hematopoietic tumors of myeloidlineage, acute myelogenous leukemias, chronic myelogenous leukemias,myelodysplastic syndrome, promyelocytic leukemia.

Yet another embodiment is a pharmaceutical composition comprising one ormore compounds having formula (I), (I-A), (IA-1), (II), (II-A), (III),(IIIA), (IIIB), (IV), (IVA) or (IVB) together with a pharmaceuticallyacceptable carrier.

DETAIL DESCRIPTION

As used herein the following definition shall apply unless otherwiseindicated. Further many of the groups defined herein can be optionallysubstituted. The listing of substituents in the definition is exemplaryand is not to be construed to limit the substituents defined elsewherein the specification.

The term ‘alkyl’ refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to eight carbon atoms, and which isattached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and1,1-dimethylethyl (t-butyl).

The term substituted or unsubstituted (C₁₋₄)alkyl refers to an alkylgroup as defined above having up to 4 carbon atoms, and the termsubstituted or unsubstituted (C₁₋₆)alkyl refers to an alkyl group asdefined above having up to 6 carbon atoms.

The term “alkenyl” refers to an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be a straight or branched orbranched chain having about 2 to about 10 carbon atoms, e.g., ethenyl,1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl,1-butenyl, and 2-butenyl.

The term substituted or unsubstituted (C₁₋₆)alkenyl refers to an alkenylgroup as defined above having up to 4 carbon atoms.

The term “alkynyl” refers to a straight or branched chain hydrocarbylradicals having at least one carbon-carbon triple bond, and having inthe range of about 2 up to 12 carbon atoms (with radicals having in therange of about 2 up to 10 carbon atoms presently being preferred) e.g.,ethynyl, propynyl, and butnyl.

The term substituted or unsubstituted (C₁₋₆) alkynyl refers to analkynyl group as defined above having up to 4 carbon atoms.

The term “alkoxy” denotes an alkyl group as defined above attached viaan oxygen linkage to the rest of the molecule. Representative examplesof these groups are —OCH₃ and —OC₂H₅. The term “substituted alkoxy”refers to an alkoxy group where the alkyl constituent is substituted(i.e., —O-(substituted alkyl) wherein the term “substituted alkyl” isthe same as defined above for “alkyl”. For example “alkoxy” refers tothe group —O-alkyl, including from 1 to 8 carbon atoms of a straight,branched, cyclic configuration and combinations thereof attached to theparent structure through oxygen. Examples include methoxy, ethoxy,propoxy, isopropoxy, cyclopropyloxy, and cyclohexyloxy.

The term “cycloalkyl” denotes a non-aromatic mono or multicyclic ringsystem of about 3 to 12 carbon atoms such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groupsinclude perhydronapththyl, adamantyl and norbornyl groups, bridgedcyclic groups, and sprirobicyclic groups, e.g., sprio (4,4) non-2-yl.

The term “C₃₋₈ cycloalkyl” refers to an cycloalkyl group as definedabove having up to 6 atoms.

The term “cycloalkylalkyl” refers to a cyclic ring-containing radicalcontaining in the range of about 3 up to 8 carbon atoms directlyattached to an alkyl group which are then attached to the main structureat any carbon from alkyl group that results in the creation of a stablestructure such as cyclopropylmethyl, cyclobuyylethyl, andcyclopentylethyl.

The term “C₃₋₆ cycloalkylalkyl” refers to an cycloalkylalkyl group asdefined above having up to 6 atoms.

The term “cycloalkenyl” refers to cyclic ring-containing radicalscontaining in the range of about 3 up to 8 carbon atoms with at leastone carbon-carbon double bond such as cyclopropenyl, cyclobutenyl, andcyclopentenyl. The term “cycloalkenylalkyl” refers to a cycloalkenylgroup directly attached to an alkyl group which are then attached to themain structure at any carbon from alkyl group that results in thecreation of a stable structure

The term “C₃₋₆ cycloalkenyl” refers to an cycloalkenyl group as definedabove having up to 6 atoms.

The term “aryl” refers to aromatic radicals having in the range of 6 upto 20 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl,and biphenyl.

The term “arylalkyl” refers to an aryl group as defined above directlybonded to an alkyl group as defined above. e.g., —CH₂C₆H₅ and —C₂H₅C₆H₅.

The term “heterocyclic ring” refers to a non-aromatic 3 to 15 memberring radical which, consists of carbon atoms and at least one heteroatomselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclic ring radicalmay be a mono-, bi-, tri- or tetracyclic ring system, which may includefused, bridged or spiro ring systems, and the nitrogen, phosphorus,carbon, oxygen or sulfur atoms in the heterocyclic ring radical may beoptionally oxidized to various oxidation states. In addition, thenitrogen atom may be optionally quaternized. The heterocyclic ringradical may be attached to the main structure at any heteroatom orcarbon atom that results in the creation of a stable structure.

The term “heterocyclyl” refers to a heterocylic ring radical as definedabove. The heterocylcyl ring radical may be attached to the mainstructure at any heteroatom or carbon atom that results in the creationof a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure. Examplesof such heterocycloalkyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl.

The term “heteroaryl” refers to an optionally substituted 5 to 14 memberaromatic ring having one or more heteroatoms selected from N, O, and Sas ring atoms. The heteroaryl may be a mono-, bi- or tricyclic ringsystem. Examples of such “heterocyclic ring” or “heteroaryl” radicalsinclude, but are not limited to, oxazolyl, thiazolyl, imidazolyl,pyrrolyl, furanyl, pyridinyl, pyrimidinyl, pyrazinyl, benzofuranyl,indolyl, benzothiazolyl, benzoxazolyl, carbazolyl, quinolyl,isoquinolyl, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxoazepinyl, azepinyl, 4-piperidonyl, pyrrolidinyl, pyridazinyl,oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiazolinyl, thiazolidinyl, isothiazolyl,quinuclidinyl, isothiazolidinyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, decahydroisoquinolyl,benzimidazolyl, thiadiazolyl, benzopyranyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl,oxadiazolyl, chromanyl, and isochromanyl. The heteroaryl ring radicalmay be attached to the main structure at any heteroatom or carbon atomthat results in the creation of a stable structure. The term“substituted heteroaryl” also includes ring systems substituted with oneor more oxide (—O—) substituents, such as pyridinyl N-oxides.

The term “heteroarylalkyl” refers to heteroaryl ring radical as definedabove directly bonded to an alkyl group. The heteroarylalkyl radical maybe attached to the main structure at any carbon atom from alkyl groupthat results in the creation of a stable structure.

The term “heterocyclylalkyl” refers to a heterocylic ring radical asdefined above directly bonded to an alkyl group. The heterocyclylalkylradical may be attached to the main structure at carbon atom in thealkyl group that results in the creation of a stable structure.

The term “cyclic ring” refers to a cyclic ring containing 3-10 carbonatoms.

The term “substituted” unless otherwise specified, refers tosubstitution with any one or any combination of the followingsubstituents and may be the same or different which one or more areselected from the groups such as hydrogen, hydroxy, halogen, carboxyl,cyano, nitro, oxo (═O), thio(═S), substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocycyl, substituted or unsubstituted heterocyclcyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, —COOR′, —C(O)R′, —C(S)R′, —C(O)NR′R″, —C(O)ONR′R″,—NR′R″, —NR′CONR′R″, —N(R′)SOR″, —N(R′)SO₂R″, —(═N—N(R′)R″),—NR′C(O)OR″, —NR′R″, —NR′C(O)R″—, —NR′C(S)R″, —NR′C(S)NR″R′″, SONR′R″—,—SO₂NR′R″—, —OR′, —OR′C(O)NR″R′″, —OR′C(O)OR″—, —OC(O)R′, —OC(O)NR′R″,—R′NR″C(O)R′″, —R′OR″, —R′C(O)OR″, —R′C(O)NR″R′″, —R′C(O)R″, R′OC(O)R″,—SR′, —SOR′, —SO₂R′, —ONO₂ wherein R′, R″ and R′″ in each of the abovegroups can be hydrogen, hydrogen, hydroxy, halogen, carboxyl, cyano,nitro, oxo (═O), thio(═S), imino (═NR′), substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocycyl, substituted or unsubstituted heterocyclcyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, or any two of R′, R″ and R′″ may be joined to form asubstituted or unsubstituted saturated or unsaturated 3-10 memberedring, which may optionally include heteroatoms which may be the same ordifferent and are selected from O, NR^(X) or S or form oxo (═O),thio(═S) or imino (═NR′). Substitution or the combinations ofsubstituents envisioned by this invention are preferably those thatresult in the formation of a stable or chemically feasible compound. Theterm stable as used herein refers to the compounds or the structure thatare not substantially altered when subjected to conditions to allow fortheir isolation, production, detection and preferably their recovery,purification and incorporation into a pharmaceutical composition.

The term “halo”, “halide”, or, alternatively, “halogen” means fluoro,chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,”“haloalkynyl” and “haloalkoxy” include alkyl, alkenyl, alkynyl andalkoxy structures that are substituted with one or more halo groups orwith combinations thereof. For example, the terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

The term “protecting group” or “PG” refers to a substituent that isemployed to block or protect a particular functionality. Otherfunctional groups on the compound may remain reactive. For example, an“amino-protecting group” is a substituent attached to an amino groupthat blocks or protects the amino functionality in the compound.Suitable amino-protecting groups include, but are not limited to,acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl(CBz) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitablehydroxy-protecting groups include, but are not limited to, acetyl andsilyl. A “carboxy-protecting group” refers to a substituent of thecarboxy group that blocks or protects the carboxy functionality.Suitable carboxy-protecting groups include, but are not limited to,—CH2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, -2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, andnitroethyl. For a general description of protecting groups and theiruse, see T. W. Greene, Protective Groups in Organic Synthesis, JohnWiley & Sons, New York, 1991.

The term “stereoisomer” refers to compounds, which have identicalchemical composition, but differ with regard to arrangement of the atomsand the groups in space. These include enantiomers, diastereomers,geometrical isomers, atropisomer or conformational isomers.

All the stereoisomers of compounds described herein are within the scopeof this invention. Racemic mixtures are also encompassed within thescope of this invention. Therefore, single stereochemical isomers aswell enantiomeric, diastereoisomeric and geometric (or conformational)mixtures of the present compounds fall within the scope of theinvention.

Certain of the compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that can be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present chemical entities,pharmaceutical compositions and methods are meant to include all suchpossible isomers, including racemic mixtures, optically pure forms andintermediate mixtures. For the instance the non-limiting example ofintermediate mixtures include a mixture of isomers in a ratio of 10:90,13:87, 17:83, 20:80, or 22:78. Optically active (R)- and (S)-isomers canbe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers.

The term “tautomers” refers to compounds, which are characterized byrelatively easy interconversion of isomeric forms in equilibrium. Theseisomers are intended to be covered by this invention. “Tautomers” arestructurally distinct isomers that interconvert by tautomerization.“Tautomerization” is a form of isomerization and includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order, often the interchange of a single bond with anadjacent double bond. Where tautomerization is possible (e.g. insolution), a chemical equilibrium of tautomers can be reached. Anexample of tautomerization is keto-enol tautomerization. A specificexample of keto-enol tautomerization is the interconversion ofpentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Anotherexample of tautomerization is phenol-keto tautomerization. A specificexample of phenol-keto tautomerization is the interconversion ofpyridin-4-ol and pyridin-4(1H)-one tautomers.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable examples of such groups unlessotherwise specified are halogen atoms and mesyloxy,p-nitrobenzensulphonyloxy and tosyloxy groups.

The term “prodrug” refers to a compound, which is an inactive precursorof a compound, converted into its active form in the body by normalmetabolic processes. Prodrug design is discussed generally in Hardma, etal. (Eds.), Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion isprovided in Higuchi, et al., Prodrugs as Novel Delivery Systems, Vol.14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers inDrug Design, American Pharmaceutical Association and Pergamon Press(1987). To illustrate, prodrugs can be converted into apharmacologically active form through hydrolysis of, for example, anester or amide linkage, thereby introducing or exposing a functionalgroup on the resultant product. The prodrugs can be designed to reactwith an endogenous compound to form a water-soluble conjugate thatfurther enhances the pharmacological properties of the compound, forexample, increased circulatory half-life. Alternatively, prodrugs can bedesigned to undergo covalent modification on a functional group with,for example, glucuronic acid, sulfate, glutathione, amino acids, oracetate. The resulting conjugate can be inactivated and excreted in theurine, or rendered more potent than the parent compound. High molecularweight conjugates also can be excreted into the bile, subjected toenzymatic cleavage, and released back into the circulation, therebyeffectively increasing the biological half-life of the originallyadministered compound.

The term “ester” refers to a compound, which is formed by reactionbetween an acid and an alcohol with elimination of water. An ester canbe represented by the general formula RCOOR′.

These prodrugs and esters are intended to be covered within the scope ofthis invention.

Additionally the instant invention also includes the compounds whichdiffer only in the presence of one or more isotopically enriched atomsfor example replacement of hydrogen with deuterium or tritium, or thereplacement of a carbon by ^(13C) or ^(14C)-enriched carbon.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are encompassedwithin the scope of the present invention.

Pharmaceutically acceptable salts forming part of this invention includesalts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu,Zn, and Mn; salts of organic bases such as N,N′-diacetylethylenediamine,glucamine, triethylamine, choline, hydroxide, dicyclohexylamine,metformin, benzylamine, trialkylamine, and thiamine; chiral bases suchas alkylphenylamine, glycinol, and phenyl glycinol; salts of naturalamino acids such as glycine, alanine, valine, leucine, isoleucine,norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, omithine, lysine, arginine, and serine; quaternaryammonium salts of the compounds of invention with alkyl halides, alkylsulphates such as MeI and (Me)₂SO₄; non-natural amino acids such asD-isomers or substituted amino acids; guanidine; and substitutedguanidine wherein the substituents are selected from nitro, amino,alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts andaluminum salts. Salts may include acid addition salts where appropriatewhich are sulphates, nitrates, phosphates, perchlorates, borates,hydrohalides, acetates, tartrates, maleates, citrates, fumarates,succinates, palmoates, methanesulphonates, benzoates, salicylates,benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange may vary from, for example, between 1% and 15% of the statednumber or numerical range. The term “comprising” (and related terms suchas “comprise” or “comprises” or “having” or “including”) includes thoseembodiments, for example, an embodiment of any composition of matter,composition, method, or process, or the like, that “consist of” or“consist essentially of” the described features.

The following abbreviations and terms have the indicated meaningsthroughout: HGFR is hepatocyte growth factor receptor; AIDS=AcquiredImmuno Deficiency Syndrome; HIV=Human Immunodeficiency Virus; MeI=MethylIodide; POCI₃=Phosphorous Oxychloride; KCNS=Potassium IsoThiocyanate;TLC=Thin Layer Chromatography; MeOH=Methanol; and CHCI₃=Chloroform.

Abbreviations used herein have their conventional meaning within thechemical and biological arts.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to an animal so that both agentsand/or their metabolites are present in the animal at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended application (in vitro or in vivo), orthe subject and disease condition being treated, e.g., the weight andage of the subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment,” “treating,” or “ameliorating” are usedinterchangeably. These terms refers to an approach for obtainingbeneficial or desired results including but not limited to therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient may still be afflicted withthe underlying disorder. For prophylactic benefit, the compositions maybe administered to a patient at risk of developing a particular disease,or to a patient reporting one or more of the physiological symptoms of adisease, even though a diagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “subject” or “patient” refers to an animal, such as a mammal,for example a human. The methods described herein can be useful in bothhuman therapeutics and veterinary applications. In some embodiments, thepatient is a mammal, and in some embodiments, the patient is human.

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or indirect interaction with the target.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes, but is not limited to, any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, one or more suitablediluents, fillers, salts, disintegrants, binders, lubricants, glidants,wetting agents, controlled release matrices, colorants/flavoring,carriers, excipients, buffers, stabilizers, solubilizers, andcombinations thereof. Except insofar as any conventional media or agentis incompatible with the active ingredient, its use in the therapeuticcompositions of the invention is contemplated. Supplementary activeingredients can also be incorporated into the compositions.

Inhibition of c-met kinase may be of therapeutic benefit in treatment ofvarious conditions, e.g., conditions characterized by an inflammatoryresponse including but not limited to autoimmune diseases, allergicdiseases, and arthritic diseases.

“Inflammatory response” as used herein is characterized by redness,heat, swelling and pain (i.e., inflammation) and typically involvestissue injury or destruction. An inflammatory response is usually alocalized, protective response elicited by injury or destruction oftissues, which serves to destroy, dilute or wall off (sequester) boththe injurious agent and the injured tissue. Inflammatory responses arenotably associated with the influx of leukocytes and/or leukocyte (e.g.,neutrophil) chemotaxis. Inflammatory responses may result from infectionwith pathogenic organisms and viruses, noninfectious means such astrauma or reperfusion following myocardial infarction or stroke, immuneresponses to foreign antigens, and autoimmune diseases. Inflammatoryresponses amenable to treatment with the methods and compounds accordingto the invention encompass conditions associated with reactions of thespecific defense system as well as conditions associated with reactionsof the non-specific defense system.

The therapeutic methods of the invention include methods for theamelioration of conditions associated with inflammatory cell activation.“Inflammatory cell activation” refers to the induction by a stimulus(including but not limited to, cytokines, antigens or auto-antibodies)of a proliferative cellular response, the production of solublemediators (including but not limited to cytokines, oxygen radicals,enzymes, prostanoids, or vasoactive amines), or cell surface expressionof new or increased numbers of mediators (including but not limited to,major histocompatibility antigens or cell adhesion molecules) ininflammatory cells (including but not limited to monocytes, macrophages,T lymphocytes, B lymphocytes, granulocytes (polymorphonuclear leukocytesincluding neutrophils, basophils, and eosinophils) mast cells, dendriticcells, Langerhans cells, and endothelial cells). It will be appreciatedby persons skilled in the art that the activation of one or acombination of these phenotypes in these cells can contribute to theinitiation, perpetuation, or exacerbation of an inflammatory condition.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents. “Transplant rejection” as usedherein refers-to any immune response directed against grafted tissue(including organs or cells (e.g., bone marrow), characterized by a lossof function of the grafted and surrounding tissues, pain, swelling,leukocytosis, and thrombocytopenia). “Allergic disease” as used hereinrefers to any symptoms, tissue damage, or loss of tissue functionresulting from allergy. “Arthritic disease” as used herein refers to anydisease that is characterized by inflammatory lesions of the jointsattributable to a variety of etiologies. “Dermatitis” as used hereinrefers to any of a large family of diseases of the skin that arecharacterized by inflammation of the skin attributable to a variety ofetiologies.

The relative efficacies of compounds as inhibitors of an enzyme activity(or other biological activity) can be established by determining theconcentrations at which each compound inhibits the activity to apredefined extent and then comparing the results. Typically, thepreferred determination is the concentration that inhibits 50% of theactivity in a biochemical assay, i.e., the 50% inhibitory concentrationor “IC50”. IC50 determinations can be accomplished using conventionaltechniques known in the art. In general, an IC50 can be determined bymeasuring the activity of a given enzyme in the presence of a range ofconcentrations of the inhibitor under study. The experimentally obtainedvalues of enzyme activity then are plotted against the inhibitorconcentrations used. The concentration of the inhibitor that shows 50%enzyme activity (as compared to the activity in the absence of anyinhibitor) is taken as the IC50 value. Analogously, other inhibitoryconcentrations can be defined through appropriate determinations ofactivity. For example, in some settings it can be desirable to establisha 90% inhibitory concentration, i.e., IC90, etc.

Accordingly, a c-met selective inhibitor alternatively can be understoodto refer to a compound that exhibits a 50% inhibitory concentration(IC50) with respect to c-met kinase, that is at least 10-fold, inanother aspect at least 20-fold, and in another aspect at least 30-fold,lower than the IC50 value with respect to any or all of the other classreceptor tyrosine kinase (RTK) family members. In an alternativeembodiment of the invention, the term c-met kinase selective inhibitorcan be understood to refer to a compound that exhibits an IC50 withrespect to c-met kinase that is at least 50-fold, in another aspect atleast 100-fold, in an additional aspect at least 200-fold, and in yetanother aspect at least 500-fold, lower than the IC50 with respect toany or all of the other RTK family members. A c-met kinase selectiveinhibitor is typically administered in an amount such that itselectively inhibits c-met activity, as described above.

The methods of the invention may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human or in a subject's body. In this context, the methods ofthe invention may be used therapeutically or prophylactically in anindividual. “Ex vivo” or “In vitro” means outside of a livingindividual. Examples of ex vivo cell populations include in vitro cellcultures and biological samples including but not limited to fluid ortissue samples obtained from individuals. Such samples may be obtainedby methods known in the art. Exemplary biological fluid samples includeblood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samplesinclude tumors and biopsies thereof. In this context, the invention maybe used for a variety of purposes, including therapeutic andexperimental purposes. For example, the invention may be used ex vivo orin vitro to determine the optimal schedule and/or dosing ofadministration of a c-met kinase selective inhibitor for a givenindication, cell type, individual, and other parameters. Informationgleaned from such use may be used for experimental or diagnosticpurposes or in the clinic to set protocols for in vivo treatment. Otherex vivo uses for which the invention may be suited are described belowor will become apparent to those skilled in the art.

Pharmaceutical Compositions

The invention provides a pharmaceutical composition comprising one ormore compounds of the present invention. The pharmaceutical compositionmay include one or more additional active ingredients as describedherein. The pharmaceutical composition may be administered for any ofthe disorders described herein

In some embodiments, the invention provides pharmaceutical compositionsfor treating diseases or conditions related to an undesirable,over-active, harmful or deleterious immune response in a mammal. Suchundesirable immune response can be associated with or result in, e.g.,asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxsis,auto-immune diseases, rhuematoid arthritis, graft versus host disease,and lupus erythematosus. The pharmaceutical compositions of the presentinvention can be used to treat other respiratory diseases including butnot limited to diseases affecting the lobes of lung, pleural cavity,bronchial tubes, trachea, upper respiratory tract, or the nerves andmuscle for breathing.

In some embodiments, the invention provides pharmaceutical compositionsfor the treatment of disorders such as hyperproliferative disorderincluding but not limited to cancer such as acute myeloid leukemia,thymus, brain, lung, squamous cell, skin, eye, retinoblastoma,intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric,stomach, pancreatic, bladder, breast, cervical, head, neck, renal,kidney, liver, ovarian, prostate, colorectal, esophageal, testicular,gynecological, thyroid, CNS, PNS, AIDS related (e.g. Lymphoma andKaposi's Sarcoma) or Viral-Induced cancer. In some embodiments, thepharmaceutical composition is for the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The invention also relates to a composition for treating a diseaserelated to vasculogenesis or angiogenesis in a mammal which can manifestas tumor angiogenesis, chronic inflammatory disease such as rheumatoidarthritis, inflammatory bowel disease, atherosclerosis, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention also provides compositions for the treatment of liverdiseases (including diabetes), pancreatitis or kidney disease (includingproliferative glomerulonephritis and diabetes-induced renal disease) orpain in a mammal.

The invention further provides a composition for the prevention ofblastocyte implantation in a mammal.

The subject pharmaceutical compositions are typically formulated toprovide a therapeutically effective amount of a compound of the presentinvention as the active ingredient, or a pharmaceutically acceptablesalt, ester, or prodrug thereof. Where desired, the pharmaceuticalcompositions contain a compound of the present invention as the activeingredient or a pharmaceutically acceptable salt and/or coordinationcomplex thereof, and one or more pharmaceutically acceptable excipients,carriers, such as inert solid diluents and fillers, diluents, includingsterile aqueous solution and various organic solvents, permeationenhancers, solubilizers and adjuvants.

The subject pharmaceutical compositions can be administered alone or incombination with one or more other agents, which are also typicallyadministered in the form of pharmaceutical compositions. Where desired,the subject compounds and other agent(s) may be mixed into a preparationor both components may be formulated into separate preparations to usethem in combination separately or at the same time.

Methods include administration of an inhibitor by itself, or incombination as described herein, and in each case optionally includingone or more suitable diluents, fillers, salts, disintegrants, binders,lubricants, glidants, wetting agents, controlled release matrices,colorants/flavoring, carriers, excipients, buffers, stabilizers,solubilizers, and combinations thereof.

Preparations of various pharmaceutical compositions are known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999), all ofwhich are incorporated by reference herein in their entirety.

The compounds or pharmaceutical composition of the present invention canbe administered by any route that enables delivery of the compounds tothe site of action, such asoral routes, intraduodenal routes, parenteralinjection (including intravenous, intraarterial, subcutaneous,intramuscular, intravascular, intraperitoneal or infusion), topicaladministration (e.g. transdermal application), rectal administration,via local delivery by catheter or stent or through inhalation. Thecompounds can also be administered intraadiposally or intrathecally.

The compositions can be administered in solid, semi-solid, liquid orgaseous form, or may be in dried powder, such as lyophilized form. Thepharmaceutical compositions can be packaged in forms convenient fordelivery, including, for example, solid dosage forms such as capsules,sachets, cachets, gelatins, papers, tablets, capsules, suppositories,pellets, pills, troches, and lozenges. The type of packaging willgenerally depend on the desired route of administration. Implantablesustained release formulations are also contemplated, as are transdermalformulations.

Routes of Administration

In the methods according to the invention, the inhibitor compounds maybe administered by various routes. For example, pharmaceuticalcompositions may be for injection, or for oral, nasal, transdermal orother forms of administration, including, e.g., by intravenous,intradermal, intramuscular, intramammary, intraperitoneal, intrathecal,intraocular, retrobulbar, intrapulmonary (e.g., aerosolized drugs) orsubcutaneous injection (including depot administration for long termrelease e.g., embedded-under the-splenic capsule, brain, or in thecornea); by sublingual, anal, or vaginal administration, or by surgicalimplantation, e.g., embedded under the splenic capsule, brain, or in thecornea. The treatment may consist of a single dose or a plurality ofdoses over a period of time. In general, the methods of the inventioninvolve administering effective amounts of a modulator of the inventiontogether with one or more pharmaceutically acceptable diluents,preservatives, solubilizers, emulsifiers, adjuvants and/or carriers, asdescribed above.

The subject pharmaceutical composition may, for example, be in a formsuitable for oral administration as a tablet, capsule, pill, powder,sustained release formulations, solution, suspension, for parenteralinjection as a sterile solution, suspension or emulsion, for topicaladministration as an ointment or cream or for rectal administration as asuppository. The pharmaceutical composition may be in unit dosage formssuitable for single administration of precise dosages. Thepharmaceutical composition will include a conventional pharmaceuticalcarrier or excipient and a compound according to the invention as anactive ingredient. In addition, it may include other medicinal orpharmaceutical agents, carriers, and adjuvants.

In one aspect, the invention provides methods for oral administration ofa pharmaceutical composition of the invention. Oral solid dosage formsare described generally in Remington's Pharmaceutical Sciences, supra atChapter 89. Solid dosage forms include tablets, capsules, pills, trochesor lozenges, and cachets or pellets. Also, liposomal or proteinoidencapsulation may be used to formulate the compositions (as, forexample, proteinoid microspheres reported in U.S. Pat. No. 4,925,673).Liposomal encapsulation may include liposomes that are derivatized withvarious polymers (e.g., U.S. Pat. No. 5,013,556). The formulation mayinclude a compound of the invention and inert ingredients which protectagainst degradation in the stomach and which permit release of thebiologically active material in the intestine.

Toxicity and therapeutic efficacy of the met kinase compounds can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., for determining the LD50 (the dose lethal to50% of the population) and the ED50 (the dose therapeutically effectivein 50% of the population). Additionally, this information can bedetermined in cell cultures or experimental animals additionally treatedwith other therapies including but not limited to radiation,chemotherapeutic agents, photodynamic therapies, radiofrequencyablation, anti-angiogenic agents, and combinations thereof.

The amount of the compound administered will be dependent on the mammalbeing treated, the severity of the disorder or condition, the rate ofadministration, the disposition of the compound and the discretion ofthe prescribing physician. However, an effective dosage is in the rangeof about 0.001 to about 100 mg per kg body weight per day, preferablyabout 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kghuman, this would amount to about 0.05 to 7 g/day, preferably about 0.05to about 2.5 g/day. In some instances, dosage levels below the lowerlimit of the aforesaid range may be more than adequate, while in othercases still larger doses may be employed without causing any harmfulside effect, e.g. by dividing such larger doses into several small dosesfor administration throughout the day.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes may be used as appropriate. A single dose of a compound ofthe invention may also be used for treatment of an acute condition.

In practice of the methods of the invention, the pharmaceuticalcompositions are generally provided in doses ranging from 1 pgcompound/kg body weight to 1000 mg/kg, 0.1 mg/kg to 100 mg/kg, 0.1 mg/kgto 50 mg/kg, and 1 to 20 mg/kg, given in daily doses or in equivalentdoses at longer or shorter intervals, e.g., every other day, twiceweekly, weekly, or twice or three times daily. The inhibitorcompositions may be administered by an initial bolus followed by acontinuous infusion to maintain therapeutic circulating levels of drugproduct. Those of ordinary skill in the art will readily optimizeeffective dosages and administration regimens as determined by goodmedical practice and the clinical condition of the individual to betreated. The frequency of dosing will depend on the pharmacokineticparameters of the agents and the route of administration. The optimalpharmaceutical formulation will be determined by one skilled in the artdepending upon the route of administration and desired dosage [see, forexample, Remington's Pharmaceutical Sciences, pp. 1435-1712, thedisclosure of which is hereby incorporated by reference]. Suchformulations may influence the physical state, stability, rate of invivo release, and rate of in vivo clearance of the administered agents.Depending on the route of administration, a suitable dose may becalculated according to body weight, body surface area or organ size.Further refinement of the calculations necessary to determine theappropriate dosage for treatment involving each of the above mentionedformulations is routinely made by those of ordinary skill in the artwithout undue experimentation, especially in light of the dosageinformation and assays disclosed herein, as well as the pharmacokineticdata observed in human clinical trials. Appropriate dosages may beascertained by using established assays for determining blood leveldosages in conjunction with an appropriate physician considering variousfactors which modify the action of drugs, e.g., the drug's specificactivity, the severity of the indication, and the responsiveness of theindividual, the age, condition, body weight, sex and diet of theindividual, the time of administration and other clinical factors. Asstudies are conducted, further information will emerge regarding theappropriate dosage levels and duration of treatment for various diseasesand conditions capable of being treated with the methods of theinvention.

In some embodiments, a compound of the invention is administered inmultiple doses. Dosing may be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing maybe about once a month, once every two weeks, once a week, or once everyother day. In another embodiment a compound of the invention and anotheragent are administered together about once per day to about 6 times perday. In another embodiment the administration of a compound of theinvention and an agent continues for less than about 7 days. In yetanother embodiment the administration continues for more than about 6,10, 14, 28 days, two months, six months, or one year. In some cases,continuous dosing is achieved and maintained as long as necessary.

Administration of the agents of the invention may continue as long asnecessary. In some embodiments, an agent of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, an agent of the invention is administered for less than 28,14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, an agent of theinvention is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

An effective amount of a compound of the invention may be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intraarterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

The compounds of the invention may be administered in dosages. It isknown in the art that due to intersubject variability in compoundpharmacokinetics, individualization of dosing regimen is necessary foroptimal therapy. Dosing for a compound of the invention may be found byroutine experimentation in light of the instant disclosure.

When a compound of the invention, is administered in a composition thatcomprises one or more agents, and the agent has a shorter half-life thanthe compound of the invention unit dose forms of the agent and thecompound of the invention may be adjusted accordingly.

The inhibitors of the invention may be covalently or noncovalentlyassociated with a carrier molecule including but not limited to a linearpolymer (e.g., polyethylene glycol, polylysine, dextran, etc.), abranched-chain polymer (see U.S. Pat. Nos. 4,289,872 and 5,229,490; PCTPublication No. WO 93/21259), a lipid, a cholesterol group (such as asteroid), or a carbohydrate or oligosaccharide. Specific examples ofcarriers for use in the pharmaceutical compositions of the inventioninclude carbohydrate-based polymers such as trehalose, mannitol,xylitol, sucrose, lactose, sorbitol, dextrans such as cyclodextran,cellulose, and cellulose derivatives. Also, the use of liposomes,microcapsules or microspheres, inclusion complexes, or other types ofcarriers is contemplated.

Other carriers include one or more water soluble polymer attachmentssuch as polyoxyethylene glycol, or polypropylene glycol as describedU.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and4,179,337. Still other useful carrier polymers known in the art includemonomethoxy-polyethylene glycol, poly-(N-vinyl pyrrolidone)-polyethyleneglycol, propylene glycol homopolymers, a polypropylene oxidelethyleneoxide co-polymer, polyoxyethylated polyols (e.g., glycerol) andpolyvinyl alcohol, as well as mixtures of these polymers.

Derivitization with bifunctional agents is useful for cross-linking acompound of the invention to a support matrix or to a carrier. One suchcarrier is polyethylene glycol (PEG). The PEG group may be of anyconvenient molecular weight and may be straight chain or branched. Theaverage molecular weight of the PEG can range from about 2 kDa to about100 kDa, in another aspect from about 5 kDa to about 50 kDa, and in afurther aspect from about 5 kDa to about 10 kDa. The PEG groups willgenerally be attached to the compounds of the invention via acylation,reductive alkylation, Michael addition, thiol alkylation or otherchemoselective conjugation/ligation methods through a reactive group onthe PEG moiety (e.g., an aldehyde, amino, ester, thiol, ci-haloacetyl,maleimido or hydrazino group) to a reactive group on the targetinhibitor compound (e.g., an aldehyde, amino, ester, thiol,a-haloacetyl, maleimido or hydrazino group). Cross-linking agents caninclude, e.g., esters with 4-azidosalicylic acid, homobifunctionalimidoesters, including disuccinimidyl esters such as 3,3′-dithiobis(succinimidylpropionate), and bifunctional maleimides such asbis-N-maleimido-1,8-octane. Derivatizing agents such asmethyl-3-[(p-azidophenyl)dithiolpropioimidate yield photoactivatableintermediates that are capable of forming crosslinks in the presence oflight. Alternatively, reactive water-insoluble matrices such as cyanogenbromide-activated carbohydrates and the reactive substrates described inU.S. Pat. Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537;and 4,330,440 may be employed for inhibitor immobilization.

Method of Treatment

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to diseases associated withmalfunctioning of c-met kinase and family.

The treatment methods provided herein comprise administering to thesubject a therapeutically effective amount of a compound of theinvention. In one embodiment, the present invention provides a method oftreating an inflammation disorder, including autoimmune diseases in amammal. The method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention.

The disorders, diseases, or conditions treatable with a compoundprovided herein, include, but are not limited to,

-   -   inflammatory or allergic diseases, including systemic        anaphylaxis and hypersensitivity disorders, atopic dermatitis,        urticaria, drug allergies, insect sting allergies, food        allergies (including celiac disease and the like), anaphylaxis,        serum sickness, drug reactions, insect venom allergies,        hypersensitivity pneumonitis, angioedema, erythema multiforme,        Stevens-Johnson syndrome, atopic keratoconjunctivitis, venereal        keratoconjunctivitis, giant papillary conjunctivitis, and        mastocytosis;    -   inflammatory bowel diseases, including Crohn's disease,        ulcerative colitis, ileitis, enteritis, and necrotizing        enterocolitis;    -   vasculitis, and Behcet's syndrome;    -   psoriasis and inflammatory dermatoses, including dermatitis,        eczema, allergic contact dermatitis, viral cutaneous pathologies        including those derived from human papillomavirus, HIV or RLV        infection, bacterial, flugal, and other parasital cutaneous        pathologies, and cutaneous lupus erythematosus;    -   asthma and respiratory allergic diseases, including allergic        asthma, exercise induced asthma, allergic rhinitis, otitis        media, hypersensitivity lung diseases, chronic obstructive        pulmonary disease and other respiratory problems;    -   autoimmune diseases and inflammatory conditions, including but        are not limited to acute disseminated encephalomyelitis (ADEM),        Addison's disease, antiphospholipid antibody syndrome (APS),        aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's        disease, Diabetes mellitus (type 1), Goodpasture's syndrome,        Graves' disease, Guillain-Barre syndrome (GBS), Reynaud's        syndrome, Hashimoto's disease, lupus erythematosus, systemic        lupus erythematosus (SLE), multiple sclerosis, myasthenia        gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis,        Ord's thyroiditis, oemphigus, polyarthritis, primary biliary        cirrhosis, psoriasis, rheumatoid arthritis, psoriatic arthritis,        gouty arthritis, spondylitis, reactive arthritis, chronic or        acute glomerulonephritis, lupus nephritis, Reiter's syndrome,        Takayasu's arteritis, temporal arteritis (also known as “giant        cell arteritis”), warm autoimmune hemolytic anemia, Wegener's        granulomatosis, alopecia universalis, Chagas' disease, chronic        fatigue syndrome, dysautonomia, endometriosis, hidradenitis        suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis,        scleroderma, ulcerative colitis, connective tissue disease,        autoimmune pulmonary inflammation, autoimmune thyroiditis,        autoimmune inflammatory eye disease, vitiligo, and vulvodynia.        Other disorders include bone-resorption disorders and        thromobsis;    -   tissue or organ transplant rejection disorders including but not        limited to graft rejection (including allograft rejection and        graft-v-host disease (GVHD)), e.g., skin graft rejection, solid        organ transplant rejection, bone marrow transplant rejection;    -   fever;    -   cardiovascular disorders, including acute heart failure,        hypotension, hypertension, angina pectoris, myocardial        infarction, cardiomyopathy, congestive heart failure,        atherosclerosis, coronary artery disease, restenosis, and        vascular stenosis;    -   cerebrovascular disorders, including traumatic brain injury,        stroke, ischemic reperfusion injury and aneurysm;    -   cancers of the breast, skin, prostate, cervix, uterus, ovary,        testes, bladder, lung, liver, larynx, oral cavity, colon and        gastrointestinal tract (e.g., esophagus, stomach, pancreas),        brain, thyroid, blood, and lymphatic system;    -   fibrosis, connective tissue disease, and sarcoidosis;    -   genital and reproductive conditions, including erectile        dysfunction;    -   gastrointestinal disorders, including gastritis, ulcers, nausea,        pancreatitis, and vomiting;    -   neurologic disorders, including Alzheimer's disease;    -   sleep disorders, including insomnia, narcolepsy, sleep apnea        syndrome, and Pickwick Syndrome;    -   pain, myalgias due to infection;    -   renal disorders;    -   ocular disorders, including glaucoma;    -   infectious diseases, including HIV;    -   sepsis; septic shock; endotoxic shock; gram negative sepsis;        gram positive sepsis; toxic shock syndrome; multiple organ        injury syndrome secondary to septicemia, trauma, or hemorrhage;    -   pulmonary or respiratory conditions including but not limited to        asthma, chronic bronchitis, allergic rhinitis, adult respiratory        distress syndrome (ARDS), severe acute respiratory syndrome        (SARS), chronic pulmonary inflammatory diseases (e.g., chronic        obstructive pulmonary disease), silicosis, pulmonary        sarcoidosis, pleurisy, alveolitis, vasculitis, pneumonia,        bronchiectasis, hereditary emphysema, and pulmonary oxygen        toxicity;    -   ischemic-reperfusion injury, e.g., of the myocardium, brain, or        extremities;    -   fibrosis including but not limited to cystic fibrosis; keloid        formation or scar tissue formation;    -   central or peripheral nervous system inflammatory conditions        including but not limited to meningitis (e.g., acute purulent        meningitis), encephalitis, and brain or spinal cord injury due        to minor trauma;    -   Sjorgren's syndrome; diseases involving leukocyte diapedesis;        alcoholic hepatitis; bacterial pneumonia; community acquired        pneumonia (CAP); Pneumocystis carinii pneumonia (PCP);        antigen-antibody complex mediated diseases; hypovolemic shock;        acute and delayed hypersensitivity; disease states due to        leukocyte dyscrasia and metastasis; thermal injury; granulocyte        transfusion associated syndromes; cytokine-induced toxicity;        stroke; pancreatitis; myocardial infarction, respiratory        syncytial virus (RSV) infection; and spinal cord injury.

In certain embodiments, the cancer or cancers treatable with the methodsprovided herein includes, but is or are not limited to,

-   -   leukemias, including, but not limited to, acute leukemia, acute        lymphocytic leukemia, acute myelocytic leukemias such as        myeloblasts, promyelocyte, myelomonocytic, monocytic,        erythroleukemia leukemias and myelodysplastic syndrome or a        symptom thereof (such as anemia, thrombocytopenia, neutropenia,        bicytopenia or pancytopenia), refractory anemia (RA), RA with        ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB        in transformation (RAEB-T), preleukemia, and chronic        myelomonocytic leukemia (CMML);    -   chronic leukemias, including, but not limited to, chronic        myelocytic (granulocytic) leukemia, chronic lymphocytic        leukemia, and hairy cell leukemia;    -   polycythemia vera;    -   lymphomas, including, but not limited to, Hodgkin's disease and        non-Hodgkin's disease;    -   multiple myelomas, including, but not limited to, smoldering        multiple myeloma, nonsecretory myeloma, osteosclerotic myeloma,        plasma cell leukemia, solitary plasmacytoma, and extramedullary        plasmacytoma;    -   Waldenstrom's macroglobulinemia;    -   monoclonal gammopathy of undetermined significance;    -   benign monoclonal gammopathy;    -   heavy chain disease;    -   bone and connective tissue sarcomas, including, but not limited        to, bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma,        malignant giant cell tumor, fibrosarcoma of bone, chordoma,        periosteal sarcoma, soft-tissue sarcomas, angiosarcoma        (hemangiosarcoma), fibrosarcoma, Kaposi's sarcoma,        leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic        cancers, neurilemmoma, rhabdomyosarcoma, and synovial sarcoma;    -   brain tumors, including, but not limited to, glioma,        astrocytoma, brain stem glioma, ependymoma, oligodendroglioma,        nonglial tumor, acoustic neurinoma, craniopharyngioma,        medulloblastoma, meningioma, pineocytoma, pineoblastoma, and        primary brain lymphoma;    -   breast cancer, including, but not limited to, adenocarcinoma,        lobular (small cell) carcinoma, intraductal carcinoma, medullary        breast cancer, mucinous breast cancer, tubular breast cancer,        papillary breast cancer, primary cancers, Paget's disease, and        inflammatory breast cancer;    -   adrenal cancer, including, but not limited to, pheochromocytom        and adrenocortical carcinoma;    -   thyroid cancer, including, but not limited to, papillary or        follicular thyroid cancer, medullary thyroid cancer, and        anaplastic thyroid cancer;    -   pancreatic cancer, including, but not limited to, insulinoma,        gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumor,        and carcinoid or islet cell tumor;    -   pituitary cancer, including, but limited to, Cushing's disease,        prolactin-secreting tumor, acromegaly, and diabetes insipidus;    -   eye cancer, including, but not limited, to ocular melanoma such        as iris melanoma, choroidal melanoma, and cilliary body        melanoma, and retinoblastoma;    -   vaginal cancer, including, but not limited to, squamous cell        carcinoma, adenocarcinoma, and melanoma;    -   vulvar cancer, including, but not limited to, squamous cell        carcinoma, melanoma, adenocarcinoma, basal cell carcinoma,        sarcoma, and Paget's disease;    -   cervical cancers, including, but not limited to, squamous cell        carcinoma, and adenocarcinoma;    -   uterine cancer, including, but not limited to, endometrial        carcinoma and uterine sarcoma;    -   ovarian cancer, including, but not limited to, ovarian        epithelial carcinoma, borderline tumor, germ cell tumor, and        stromal tumor;    -   esophageal cancer, including, but not limited to, squamous        cancer, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid        carcinoma, adenosquamous carcinoma, sarcoma, melanoma,        plasmacytoma, verrucous carcinoma, and oat cell (small cell)        carcinoma;    -   stomach cancer, including, but not limited to, adenocarcinoma,        fungating (polypoid), ulcerating, superficial spreading,        diffusely spreading, malignant lymphoma, liposarcoma,        fibrosarcoma, and carcinosarcoma;    -   colon cancer;    -   rectal cancer;    -   liver cancer, including, but not limited to, hepatocellular        carcinoma and hepatoblastoma;    -   gallbladder cancer, including, but not limited to,        adenocarcinoma;    -   cholangiocarcinomas, including, but not limited to, pappillary,        nodular, and diffuse;    -   lung cancer, including, but not limited to, non-small cell lung        cancer, squamous cell carcinoma (epidermoid carcinoma),        adenocarcinoma, large-cell carcinoma, and small-cell lung        cancer;    -   testicular cancer, including, but not limited to, germinal        tumor, seminoma, anaplastic, classic (typical), spermatocytic,        nonseminoma, embryonal carcinoma, teratoma carcinoma, and        choriocarcinoma (yolk-sac tumor);    -   prostate cancer, including, but not limited to, adenocarcinoma,        leiomyosarcoma, and rhabdomyosarcoma;    -   penal cancer;    -   oral cancer, including, but not limited to, squamous cell        carcinoma;    -   basal cancer;    -   salivary gland cancer, including, but not limited to,        adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic        carcinoma;    -   pharynx cancer, including, but not limited to, squamous cell        cancer and verrucous;    -   skin cancer, including, but not limited to, basal cell        carcinoma, squamous cell carcinoma and melanoma, superficial        spreading melanoma, nodular melanoma, lentigo malignant        melanoma, and acral lentiginous melanoma;    -   kidney cancer, including, but not limited to, renal cell cancer,        adenocarcinoma,    -   hypernephroma, fibrosarcoma, and transitional cell cancer (renal        pelvis and/or uterer);    -   Wilms' tumor;    -   bladder cancer, including, but not limited to, transitional cell        carcinoma, squamous cell cancer, adenocarcinoma, and        carcinosarcoma; and other cancer, including, not limited to,        myxosarcoma, osteogenic sarcoma, endotheliosarcoma,        lymphangio-endotheliosarcoma, mesothelioma, synovioma,        hemangioblastoma, epithelial carcinoma, cystadenocarcinoma,        bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland        carcinoma, papillary carcinoma, and papillary adenocarcinomas        See Fishman et al., 1985, Medicine, 2d Ed., J.B. Lippincott Co.,        Philadelphia and Murphy et al., 1997, Informed Decisions: The        Complete Book of Cancer Diagnosis, Treatment, and Recovery,        Viking Penguin, Penguin Books U.S.A., Inc., United States of        America.

It will be appreciated that the treatment methods of the invention areuseful in the fields of human medicine and veterinary medicine. Thus,the individual to be treated may be a mammal, preferably human, or otheranimals. For veterinary purposes, individuals include but are notlimited to farm animals including cows, sheep, pigs, horses, and goats;companion animals such as dogs and cats; exotic and/or zoo animals;laboratory animals including mice, rats, rabbits, guinea pigs, andhamsters; and poultry such as chickens, turkeys, ducks, and geese.

In another embodiment, the compounds described herein are used for thetreatment of cancer such as acute myeloid leukemia, thymus, brain, lung,squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oralcavity and oropharyngeal, bladder, gastric, stomach, pancreatic,bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian,prostate, colorectal, esophageal, testicular, gynecological, thyroid,CNS, PNS, AIDS-related (e.g. Lymphoma and Kaposi's Sarcoma) orviral-induced cancer. In some embodiments, said method relates to thetreatment of a non-cancerous hyperproliferative disorder such as benignhyperplasia of the skin (e.g., psoriasis), restenosis, or prostate(e.g., benign prostatic hypertrophy (BPH)).

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal that comprises administeringto said mammal a therapeutically effective amount of a compound of thepresent invention. In some embodiments, said method is for treating adisease selected from the group consisting of tumor angiogenesis,chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer.

Patients that can be treated with compounds of the present invention,according to the methods of this invention include, for example,patients that have been diagnosed as having psoriasis; restenosis;atherosclerosis; BPH; breast cancer such as a ductal carcinoma in ducttissue in a mammary gland, medullary carcinomas, colloid carcinomas,tubular carcinomas, and inflammatory breast cancer; ovarian cancer,including epithelial ovarian tumors such as adenocarcinoma in the ovaryand an adenocarcinoma that has migrated from the ovary into theabdominal cavity; uterine cancer; cervical cancer such as adenocarcinomain the cervix epithelial including squamous cell carcinoma andadenocarcinomas; prostate cancer, such as a prostate cancer selectedfrom the following: an adenocarcinoma or an adenocarinoma that hasmigrated to the bone; pancreatic cancer such as epitheliod carcinoma inthe pancreatic duct tissue and an adenocarcinoma in a pancreatic duct;bladder cancer such as a transitional cell carcinoma in urinary bladder,urothelial carcinomas (transitional cell carcinomas), tumors in theurothelial cells that line the bladder, squamous cell carcinomas,adenocarcinomas, and small cell cancers; leukemia such as acute myeloidleukemia (AML), acute lymphocytic leukemia, chronic lymphocyticleukemia, chronic myeloid leukemia, hairy cell leukemia, myelodysplasia,myeloproliferative disorders, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia(CLL), multiple myeloma (MM), and myelodysplastic syndrome (MDS); bonecancer; lung cancer such as non-small cell lung cancer (NSCLC), which isdivided into squamous cell carcinomas, adenocarcinomas, and large cellundifferentiated carcinomas, and small cell lung cancer; skin cancersuch as basal cell carcinoma, melanoma, squamous cell carcinoma andactinic keratosis, which is a skin condition that sometimes developsinto squamous cell carcinoma; eye retinoblastoma; cutaneous orintraocular (eye) melanoma; primary liver cancer (cancer that begins inthe liver); kidney cancer; thyroid cancer such as papillary, follicular,medullary and anaplastic; AIDS-related lymphoma such as diffuse largeB-cell lymphoma, B-cell immunoblastic lymphoma and small non-cleavedcell lymphoma; Kaposi's Sarcoma; viral-induced cancers includinghepatitis B virus (HBV), hepatitis C virus (HCV), and hepatocellularcarcinoma; human lymphotropic virus-type 1 (HTLV-I) and adult T-cellleukemia/lymphoma; and human papilloma virus (HPV) and cervical cancer;central nervous system cancers (CNS) such as primary brain tumor, whichincludes gliomas (astrocytoma, anaplastic astrocytoma, or glioblastomamultiforme), Oligodendroglioma, Ependymoma, Meningioma, Lymphoma,Schwannoma, and Medulloblastoma; peripheral nervous system (PNS) cancerssuch as acoustic neuromas and malignant peripheral nerve sheath tumor(MPNST) including neurofibromas and schwannomas, malignant fibrouscytoma, malignant fibrous histiocytoma, malignant meningioma, malignantmesothelioma, and malignant mixed Müllerian tumor; oral cavity andoropharyngeal cancer such as, hypopharyngeal cancer, laryngeal cancer,nasopharyngeal cancer, and oropharyngeal cancer; stomach cancer such aslymphomas, gastric stromal tumors, and carcinoid tumors; testicularcancer such as germ cell tumors (GCTs), which include seminomas andnonseminomas, and gonadal stromal tumors, which include Leydig celltumors and Sertoli cell tumors; thymus cancer such as to thymomas,thymic carcinomas, Hodgkin disease, non-Hodgkin lymphomas carcinoids orcarcinoid tumors; rectal cancer; and colon cancer.

The invention also relates to a method of treating diabetes in a mammalthat comprises administering to said mammal a therapeutically effectiveamount of a compound of the present invention.

In addition, the compounds described herein may be used to treat acne.

In addition, the compounds described herein may be used for thetreatment of arteriosclerosis, including atherosclerosis.Arteriosclerosis is a general term describing any hardening of medium orlarge arteries. Atherosclerosis is a hardening of an artery specificallydue to an atheromatous plaque.

Further the compounds described herein may be used for the treatment ofglomerulonephritis. Glomerulonephritis is a primary or secondaryautoimmune renal disease characterized by inflammation of the glomeruli.It may be asymptomatic, or present with hematuria and/or proteinuria.There are many recognized types, divided in acute, subacute or chronicglomerulonephritis. Causes are infectious (bacterial, viral or parasiticpathogens), autoimmune or paraneoplastic.

Additionally, the compounds described herein may be used for thetreatment of bursitis, lupus, acute disseminated encephalomyelitis(ADEM), addison's disease, antiphospholipid antibody syndrome (APS),aplastic anemia, autoimmune hepatitis, coeliac disease, Crohn's disease,diabetes mellitus (type 1), goodpasture's syndrome, graves' disease,guillain-barre syndrome (GBS), hashimoto's disease, inflammatory boweldisease, lupus erythematosus, myasthenia gravis, opsoclonus myoclonussyndrome (OMS), optic neuritis, ord's thyroiditiSjOstheoarthritis,uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis,reiter's syndrome, takayasu's arteritis, temporal arteritis, warmautoimmune hemolytic anemia, Wegener's granulomatosis, alopeciauniversalis, chagas¹ disease, chronic fatigue syndrome, dysautonomia,endometriosis, hidradenitis suppurativa, interstitial cystitis,neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo,vulvodynia, appendicitis, arteritis, arthritis, blepharitis,bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis,chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis,laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

The invention also relates to a method of treating a cardiovasculardisease in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention.Examples of cardiovascular conditions include, but are not limited to,atherosclerosis, restenosis, vascular occlusion and carotid obstructivedisease.

In another aspect, the present invention provides methods of disruptingthe function of a leukocyte or disrupting a function of an osteoclast.The method includes contacting the leukocyte or the osteoclast with afunction disrupting amount of a compound of the invention.

In another aspect of the present invention, methods are provided fortreating ophthalmic disease by administering one or more of the subjectcompounds or pharmaceutical compositions to the eye of a subject.

The invention further provides methods of modulating kinase activity bycontacting a kinase with an amount of a compound of the inventionsufficient to modulate the activity of the kinase. Modulate can beinhibiting or activating kinase activity. In some embodiments, theinvention provides methods of inhibiting kinase activity by contacting akinase with an amount of a compound of the invention sufficient toinhibit the activity of the kinase. In some embodiments, the inventionprovides methods of inhibiting kinase activity in a solution bycontacting said solution with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said solution. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in a cell by contacting said cell with an amount of a compoundof the invention sufficient to inhibit the activity of the kinase insaid cell. In some embodiments, the invention provides methods ofinhibiting kinase activity in a tissue by contacting said tissue with anamount of a compound of the invention sufficient to inhibit the activityof the kinase in said tissue. In some embodiments, the inventionprovides methods of inhibiting kinase activity in an organism bycontacting said organism with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said organism. Insome embodiments, the invention provides methods of inhibiting kinaseactivity in an animal by contacting said animal with an amount of acompound of the invention sufficient to inhibit the activity of thekinase in said animal. In some embodiments, the invention providesmethods of inhibiting kinase activity in a mammal by contacting saidmammal with an amount of a compound of the invention sufficient toinhibit the activity of the kinase in said mammal. In some embodiments,the invention provides methods of inhibiting kinase activity in a humanby contacting said human with an amount of a compound of the inventionsufficient to inhibit the activity of the kinase in said human. In someembodiments, the % of kinase activity after contacting a kinase with acompound of the invention is less than 1, 5, 10, 20, 30, 40, 50, 60, 70,80, 90, 95, or 99% of the kinase activity in the absence of saidcontacting step.

In some embodiments, the kinase is a pretein kinase, more particularly anon-receptor or receptor tyrosine protein kinase. In some embodiments,the kinase is selected from the group consisting of C-met includingmutants if any; AbI, VEGFR, Ephrin receptor B4 (EphB4); TEK receptortyrosine kinase (HE2); FMS-related tyrosine kinase 3 (FLT-3); Plateletderived growth factor receptor (PDGFR); RET; ATM; ATR; hSmg-1; Hck; Src;Epidermal growth factor receptor (EGFR); KIT; Inulsin Receptor (IR) andIGFR.

The invention further provides methods of modulating c-met kinaseactivity by contacting a c-met kinase with an amount of a compound ofthe invention sufficient to modulate the activity of the c-met kinase.Modulate can be inhibiting or activating c-met kinase activity. In someembodiments, the invention provides methods of inhibiting c-met kinaseactivity by contacting a c-met kinase with an amount of a compound ofthe invention sufficient to inhibit the activity of the c-met kinase. Insome embodiments, the invention provides methods of inhibiting c-metkinase activity. Such inhibition can take place in solution, in a cellexpressing one or more c-met kinase, in a tissue comprising a cellexpressing one or more c-met kinases, or in an organism expressing oneor more c-met kinase. In some embodiments, the invention providesmethods of inhibiting c-met kinase activity in an animal (includingmammal such as humans) by contacting said animal with an amount of acompound of the invention sufficient to inhibit the activity of thec-met kinase in said animal.

Combination Treatment

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention. In one aspect,such therapy includes but is not limited to the combination of thesubject compound with chemotherapeutic agents, therapeutic antibodies,and radiation treatment, to provide a synergistic or additivetherapeutic effect.

For treatment of autoimmune diseases, the subject compounds orpharmaceutical compositions can be used in combination with commonlyprescribed drugs including but not limited to Enbrel®, Remicade®,Humira®, Avonex®, and Rebif®. For treatment of respiratory diseases, thesubject compounds or pharmaceutical compositions can be administered incombination with commonly prescribed drugs including but not limited toXolair®, Advair®, Singulair®, and Spiriva®.

The compounds of the invention may be formulated or administered inconjunction with other agents that act to relieve the symptoms ofinflammatory conditions such as encephalomyelitis, asthma, and the otherdiseases described herein. These agents include non-steroidalanti-inflammatory drugs (NSAIDs), e.g. acetylsalicylic acid; ibuprofen;naproxen; indomethacin; nabumetone; tolmetin; etc. Corticosteroids areused to reduce inflammation and suppress activity of the immune system.The most commonly prescribed drug of this type is Prednisone.Chloroquine (Aralen) or hydroxychloroquine (Plaquenil) may also be veryuseful in some individuals with lupus. They are most often prescribedfor skin and joint symptoms of lupus. Azathioprine (Imuran) andcyclophosphamide (Cytoxan) suppress inflammation and tend to suppressthe immune system. Other agents, e.g. methotrexate and cyclosporin areused to control the symptoms of lupus. Anticoagulants are employed toprevent blood from clotting rapidly. They range from aspirin at very lowdose which prevents platelets from sticking, to heparin/coumadin.

In another one aspect, this invention also relates to a pharmaceuticalcomposition for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of the present invention, incombination with an amount of an anti-cancer agent (e.g. achemotherapeutic agent). Many chemotherapeutics are presently known inthe art and can be used in combination with the compounds of theinvention.

In some embodiments, the chemotherapeutic is selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec (Imatinib Mesylate), Velcade(bortezomib), Iressa (gefitinib), Sprycel (Dasatinib), and Adriamycin aswell as a host of chemotherapeutic agents. Non-limiting examples ofchemotherapeutic agents include alkylating agents such as thiotepa andcyclosphosphamide (CYTOXAN™); alkyl sulfonates such as busulfan,improsulfan and piposulfan; aziridines such as benzodopa, carboquone,meturedopa, and uredopa; ethylenimines and methylamelamines includingaltretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, pκ)tfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.R™-; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide (Casodex), leuprolide, andgoserelin (Zoladex); chlorambucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum analogs such as cisplatin andcarboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide;mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine;novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate;camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO), 17α-Ethinylestradiol,Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone,Megestrolacetate, Methylprednisolone, Methyl-testosterone, Prednisolone,Triamcinolone, chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Medroxyprogesteroneacetate, matrix metalloproteinase inhibitors, EGFRinhibitors, Pan Her inhibitors, VEGF inhibitors, including as anti-VEGFantibodies such as Avastin, and small molecules such as ZD6474 andSU6668, vatalanib, BAY-43-9006, SU11248, CP-547632, and CEP-7055.Anti-Her2 antibodies (such as Herceptin from Genentech) may also beutilized. Suitable EGFR inhibitors include gefitinib, erlotinib, andcetuximab. Pan Her inhibitors include canertinib, EKB-569, andGW-572016. Further suitable anticancer agents include, but are notlimited to, Src inhibitors, MEK-1 kinase inhibitors, MAPK kinaseinhibitors, PI3 kinase inhibitors, and PDGF inhibitors, such asimatinib. Also included are anti-angiogenic and antivascular agentswhich, by interrupting blood flow to solid tumors, render cancer cellsquiescent by depriving them of nutrition. Castration which also rendersandrogen dependent carcinomas non-proliferative, may also be utilized.Also included are IGF1R inhibitors, inhibitors of non-receptor andreceptor tyrosine kinases, and inhibitors of integrin signalling.Additional anticancer agents include microtubule-stabilizing agents7-O-methylthiomethylpaclitaxel (disclosed in U.S. Pat. No. 5,646,176),4-desacetyl-4-methylcarbonatepaclitaxel,3′-tert-butyl-3′-N-tert-butyloxycarbonyl-4-desacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel(disclosed in U.S. Ser. No. 09/712,352 filed on Nov. 14, 2000), C-4methyl carbonate paclitaxel, epothilone A, epothilone B, epothilone C,epothilone D, desoxyepothilone A, desoxyepothilone B,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo [14.1.0]heptadecane-5,9-dione (disclosed in WO 99/02514),[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabicyclo[14.1.0]-heptadecane-5,-9-dione(as disclosed in U.S. Pat. No. 6,262,094) and derivatives thereof; andmicrotubule-disruptor agents. Also suitable are CDK inhibitors, anantiproliferative cell cycle inhibitor, epidophyllotoxin; anantineoplastic enzyme; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Additional cytotoxic agents include, hexamethyl melamine, idatrexate,L-asparaginase, camptothecin, topotecan, pyridobenzoindole derivatives,interferons, and interleukins. Where desired, the compounds orpharmaceutical composition of the present invention can be used incombination with commonly prescribed anti-cancer drugs such asHerceptin®, Avastin®, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®,and Velcade®

This invention further relates to a method for using the compounds orpharmaceutical composition in combination with radiation therapy ininhibiting abnormal cell growth or treating the hyperproliferativedisorder in the mammal. Techniques for administering radiation therapyare known in the art, and these techniques can be used in thecombination therapy described herein. The administration of the compoundof the invention in this combination therapy can be determined asdescribed herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as 1-125, 1-131, Yb-169, Ir-192 as a solid source,1-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any 5 solution of radionuclides),e.g., a solution of 1-125 or 1-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention, which amount is effective is sensitizing abnormalcells to treatment with radiation.

The compounds or pharmaceutical compositions of the present inventioncan be used in combination with an amount of one or more substancesselected from anti-angiogenesis agents, signal transduction inhibitors,and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-H(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the present invention and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-I. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i.e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the present inventionare AG-3340, RO 32-3555, and RS 13-0830.

The invention also relates to a method of and to a pharmaceuticalcomposition of treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the present invention, or anisotopically-labeled derivative thereof, and an amount of one or moretherapeutic agents use for the treatment of cardiovascular diseases.

Examples for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, antiproliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-Lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include but are not limited to anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

Further therapeutic agents that can be combined with a subject compoundmay be found in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” Tenth Edition edited by Hardman, Limbird and Gilman or thePhysician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the compounds of theinvention will be co-administered with other agents as described above.When used in combination therapy, the compounds described herein may beadministered with the second agent simultaneously or separately. Thisadministration in combination can include simultaneous administration ofthe two agents in the same dosage form, simultaneous administration inseparate dosage forms, and separate administration. That is, a compounddescribed herein and any of the agents described above can be formulatedtogether in the same dosage form and administered simultaneously.Alternatively, a compound of the present invention and any of the agentsdescribed above can be simultaneously administered, wherein both theagents are present in separate formulations. In another alternative, acompound of the present invention can be administered just followed byand any of the agents described above, or vice versa. In the separateadministration protocol, a compound of the present invention and any ofthe agents described above may be administered a few minutes apart, or afew hours apart, or a few days apart.

The methods in accordance with the invention may include administering ac-met kinase selective inhibitor with one or more other agents thateither enhance the activity of the inhibitor or compliment its activityor use in treatment. Such additional factors and/or agents may producean augmented or even synergistic effect when administered with a c-metkinase selective inhibitor, or minimize side effects.

In one embodiment, the methods of the invention may includeadministering formulations comprising a c-met kinase selective inhibitorof the invention with a particular cytokine, lymphokine, otherhematopoietic factor, thrombolytic or anti-thrombotic factor, oranti-inflammatory agent before, during, or after administration of thec-met kinase inhibitor. One of ordinary skill can easily determine if aparticular cytokine, lymphokine, hematopoietic factor, thrombolytic ofanti-thrombotic factor, and/or anti-inflammatory agent enhances orcompliments the activity or use of the c-met kinase inhibitors intreatment.

More specifically, and without limitation, the methods of the inventionmay comprise administering a c-met kinase selective inhibitor with oneor more of TNF, IL-1, IL-2, IL-3, IL4, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IFN,G-CSF, Meg-CSF, GM-CSF, thrombopoietin, stem cell factor, anderythropoietin. Compositions in accordance with the invention may alsoinclude other known angiopoietins such as Ang-2, Ang4, and Ang-Y, growthfactors such as bone morphogenic protein-1, bone morphogenic protein-2,bone morphogenic protein-3, bone morphogenic protein-4, bone morphogenicprotein-5, bone morphogenic protein-6, bone morphogenic protein-7, bonemorphogenic protein-8, bone morphogenic protein-9, bone morphogenicprotein-10, bone morphogenic protein-11, bone morphogenic protein-12,bone morphogenic protein-13, bone morphogenic protein-14, bonemorphogenic protein-15, bone morphogenic protein receptor IA, bonemorphogenic protein receptor IB, brain derived neurotrophic factor,ciliary neutrophic factor, ciliary neutrophic factor receptor a,cytokine-induced neutrophil chemotactic factor 1, cytokine-inducedneutrophil chemotactic factor 2 alpha, cytokine-induced neutrophilchemotactic factor 2 beta, beta endothelial cell growth factor,endothelin 1, epidermal growth factor, epithelial-derived neutrophilattractant, fibroblast growth factor 4, fibroblast growth factor 5,fibroblast growth factor 6, fibroblast growth factor 7, fibroblastgrowth factor 8, fibroblast growth factor 8b, fibroblast growth factor8c, fibroblast growth factor 9, fibroblast growth factor 10, fibroblastgrowth factor acidic, fibroblast growth factor basic, glial cellline-derived neutrophic factor receptor a1, glial cell line-derivedneutrophic factor receptor a2, growth related protein, growth relatedprotein a, growth related protein .beta., growth related protein.gamma., heparin binding epidermal growth factor, hepatocyte growthfactor, hepatocyte growth factor receptor, insulin-like growth factor I,insulin-like growth factor receptor, insulin-like growth factor II,insulin-like growth factor binding protein, keratinocyte growth factor,leukemia inhibitory factor, leukemia inhibitory factor receptor alpha,nerve growth factor, nerve growth factor receptor, neurotrophin-3,neurptrophin-4, placenta growth factor, placenta growth factor 2,platelet derived endothelial cell growth factor, platelet derived growthfactor, platelet derived growth factor A chain, platelet derived growthfactor AA, platelet derived growth factor AB, platelet derived growthfactor B chain, platelet derived growth factor BB, platelet derivedgrowth factor receptor a, platelet derived growth factor receptor beta,pre-B cell growth stimulating factor, stem cell factor, stem cell factorreceptor, transforming growth factor alpha, transforming growth factorbeta, transforming growth factor beta 1, transforming growth factor beta1.2, transforming growth factor beta 2, transforming growth factor beta3, transforming growth factor beta 5, latent transforming growth factorbeta 1, transforming growth factor beta binding protein I, transforminggrowth factor beta binding protein II, transforming growth factor betabinding protein III, tumor necrosis factor receptor type I, tumornecrosis factor receptor type II, urokinase-type plasminogen activatorreceptor, and chimeric proteins and biologically or immunologicallyactive fragments thereof.

The following general methodology described herein provides the mannerand process of making and using the compound of the present inventionand are illustrative rather than limiting. Further modification ofprovided methodology and additionally new methods may also be devised inorder to achieve and serve the purpose of the invention. Accordingly, itshould be understood that there may be other embodiments which fallwithin the spirit and scope of the invention as defined by thespecification hereto.

Representative compounds of the present invention include thosespecified above in Table 1 and pharmaceutically acceptable saltsthereof. The present invention also includes the intermediate compoundsdiscussed in the examples and elsewhere in the specification as well astheir salts. The present invention should not be construed to be limitedto them.

General Method of Preparation of Compounds of the Invention

The compounds of the present invention may be prepared by the followingprocesses. Unless otherwise indicated, the variables (e.g. Cy¹, R², L₂,X, and Cy²) when used in the below formulae are to be understood topresent those groups described above in relation to formula (I).

Scheme 1:

This scheme provides a method for the preparation of the compound offormula (IA) wherein L₂ is —CR^(a)R^(b)—, X is CR¹ or N and the othervariables such as Cy¹, R², and Cy² are the same as described above inrelation to formula (I).

The compound of formula (1) wherein Hal represents a halogen and R² isthe same as described above in relation to formula (I) can be coupledwith a compound of formula Cy²-L₂-NH₂ in the presence of a suitablebase, such as sodium or potassium carbonate, to give a compound offormula (2) wherein L₂ is —CR^(a)R^(b)—. The compound of formula (2) canthen be converted to a compound of formula (3) by reducing with a metalsuch as iron, or a metal halide such as stannous chloride and an acid(such as acetic acid, hydrochloric acid or ammonium chloride). Thecompound of formula (3) can then be cyclised to a compound of formula(4) wherein X═N using nitrous acid, generated in situ by reacting analkali metal nitrite such as sodium nitrite with an acid such as aceticacid or hydrochloric acid. The compound of formula (3) can also becyclised to form a compound of formula (4) wherein X═CR¹, by heating orirradiating with microwaves in the presence of R¹COOH wherein R¹ is H ora C₁-C₄ alkyl group. The compound of formula (4) can be coupled with aboronic acid of formula Cy¹-B(OR)₂ (wherein R═H) or its ester (whereinR=alkyl) in the presence of a transition metal catalyst such astetrakis(triphenylphosphine)palladium(0) and a suitable base such aspotassium carbonate to give the desired compounds of formula (IA)wherein L₂ is —CR^(a)R^(b)—, X is CR¹ or N and the other variables suchas Cy¹, R² and Cy² are the same as described above in relation toformula (I)

Alternatively, the compound of formula (2) may be coupled with a boronicacid of formula Cy¹-B(OR)₂ (wherein R═H) or its ester (wherein R=alkyl)in the presence of a catalyst such astetrakis(triphenylphosphine)palladium(0) and a suitable base such aspotassium carbonate to give a compound of formula (5). The compound offormula (5) can then be converted to a compound of formula (6) byreducing with a metal such as iron, or a metal halide such as stannouschloride and an acid such as acetic acid, hydrochloric acid or ammoniumchloride. The compound of formula (6) can then be cyclised to a compoundof formula (IA) wherein X═N using nitrous acid, generated in situ byreacting an alkali metal nitrite such as sodium nitrite with an acidsuch as acetic acid or hydrochloric acid. The compound of formula (6)can also be cyclised to a compound of formula (IA) wherein X═CR¹, byheating or irradiating with microwaves in the presence of R′COOH whereinR¹ is H or a C₁-C₄ alkyl group.

Scheme 2:

This scheme provides a method for the preparation of a compound offormula (IA-1) wherein D is substituted or unsubstituted monocyclic arylor substituted or unsubstituted monocyclic heteroaryl and the othervariables such as L₂, R², X, and Cy² are the same as described above inrelation to formula (IA-1):

A compound of formula (4) can be coupled with a boronic acid of formula7 (wherein R═H) or its ester (wherein R=alkyl) in the presence of atransition metal catalyst such astetrakis(triphenylphosphine)palladium(0) and a suitable base such aspotassium carbonate to give compound of formula (IA-1).

Schemes 2A and 2B provide a non-limiting specific illustration coveringsome of the embodiments of the compound of formula (IA-1).

Scheme 2A:

This scheme provides a method for the preparation of a compound offormula (IA-1) wherein D is a substituted phenyl. In particular thephenyl ring is substituted with a group of formula COOR^(x) (referred toas a compound of formula (IA-1a)) or CONR^(x)R^(y) (referred to as acompound of formula (IA-1b)) wherein R^(x) and R^(y) are the same asdescribed herein. Optionally the phenyl ring is further substituted withone or more R′ wherein each R′ is independently hydrogen, halogen orsubstituted or unsubstituted alkyl.

The compound of formula (4) can be coupled with a boronic acid offormula 8 (wherein R═H) or its ester (wherein R=alkyl) in the presenceof a transition metal catalyst such astetrakis(triphenylphosphine)palladium(0) and a suitable base such aspotassium carbonate to give the compound of formula (9). The compound offormula (9) can be hydrolysed in the presence of an alkali metalhydroxide such as lithium hydroxide to give the compound of formula(1A-1a). The compound of formula (IA-1a) can be converted into acompound of formula (IA-1b) by reacting it with an amine of the formulaR^(x)R^(y)NH in the presence of an amide coupling reagent such asN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl),(benzotriazol-1yl)oxytris(dimethylamino)phosphonium hexafluorophosphate(BOP) or any other amide coupling reagent known in the art.Alternatively the conversion can be effected by reacting the compound offormula (IA-1a) with a halogenating agent such as thionyl chloride andsubsequently reacting the resultant acid halide with an amine of theformula R^(x)R^(y)NH in the presence of a suitable base such as atrialkylamine. The compounds of formula (IA-1b) can also be obtained byreacting the compound of formula 4 with a boronic acid of formula 10(wherein R═H) or its ester (wherein R=alkyl).

Scheme 2B:

This scheme provides a method for the preparation of compound of formula(IA-1) wherein D is a pyrazole (refered to as compound of formula(IA-1c)) or substituted Pyrazole referred to as compound of formula(IA-1d). In particular the pyrazole ring is substituted with substitutedor unsubstituted alkyl. Optionally the said pyrazole ring is furthersubstituted with one or more of R′; wherein R′ is hydrogen, halogen orsubstituted or unsubstituted alkyl.

The compound of formula (4) can be coupled with a boronic acid offormula 11 (wherein R═H) or its ester (wherein R=alkyl) in the presenceof a transition metal catalyst such astetrakis(triphenylphosphine)palladium(0) and a suitable base such aspotassium carbonate to give compound of formula (IA-1c). The compound offormula (IA-1c) can be alkylated with an alkyl halide of formula R′Xwherein R′ is substituted or unsubstituted alkyl in the presence of asuitable base such as a metal hydride to give the compound of formula(IA-1d).

Scheme 3:

This scheme provides a method for the preparation of the compound offormula (II) and (IIA) wherein A is —OR^(c) or R^(c)R—N—, L₂ is—CR^(a)R^(b)—, X is CR¹ or N and the other variables such as R², and Cy²are the same as described above in relation to formula (II) and (IIA).

The compound of formula (4) can be reacted with a nucleophilic compoundof formula AH wherein A is —OR^(c) or R^(c)R—N, in the presence of abase such as an alkali metal fluoride, alkali metal carbonate or analkali metal alkoxide to give a compound of formula (II). Optionallythis reaction may be carried out in the presence of a transition metalcatalyst such as palladium acetate and a phosphine ligand such astriphenyl phosphine.

Scheme 4:

This scheme provides a method for the preparation of a compound offormula (III) wherein L₂ is —CR^(a)R^(b)—, X is CR¹ or N, U is C—CR³, Vis N, W is O or NR⁴ and the other variables such as R⁵, R², and Cy² arethe same as described above in relation to formula (III).

The compound of formula (4) can be reacted with a tin compound offormula 12 wherein R^(a) and R^(b) are (optionally R^(a) and R^(b) canalso be alkyl or aryl) in the presence of a transition metal catalystsuch as tris(dibenzylidineacetone)palladium(0) and optionally in thepresence of a ligand such as triphenylphosphine to give the compound offormula (4a). The compound of formula (4a) can be reacted with thecompound of formula R⁵—W—NH₂ or R⁵ ₂NCO wherein R⁵ is as defined hereinabove and W is O, S or NR⁴ to give the desired compound of formula(III).

Similar methodologies with certain modifications as known to thoseskilled in the art can be used to synthesize compounds of formula (I),(IA), (IA-1) (II), (IIA), (III), (IIIA), (IIIB) and (IV) wherein all thevariables are to be understood to present those groups described abovein relation to formula (I), (IA), (IA-1) (II), (IIA), (III), (IIIA),(IIIB) and (IV) using suitable intermediates and reagents.

EXPERIMENTAL

Unless otherwise mentioned, work-up implies distribution of reactionmixture between the aqueous and organic phases indicated withinparenthesis, separation and drying over Na₂SO₄ of the organic layer andevaporating the solvent to give a residue. Unless otherwise stated,purification implies column chromatography using silica gel as thestationary phase and a mixture of petroleum ether (boiling at 60-80° C.)and ethyl acetate or dichloromethane and methanol of suitable polarityas the mobile phases. RT implies ambient temperature (25-28° C.).

Intermediate 1: Quinolin-6-ylmethanamine Step 1: Quinoline-6-carboxylicAcid

To a mixture of 4-aminobenzoic acid (175 g, 1.28 mol), 4-nitrophenol(88.75 g, 0.64 mol) and sulphuric acid (1.2 lit.), glycerol (234.8 g,2.55 mol) was added dropwise at 135° C. After 48 h, the reaction mixturewas cooled to 0° C. and the pH adjusted to 3-5 with 10% sodium hydroxidesolution. The resulting precipitate was collected by filtration andwashed with water and dried under vacuum to afford the title compound asa black solid (125 g, 56%).

Step 2: Methyl quinoline-6-carboxylate

To a solution of quinoline-6-carboxylic acid (183 g, 1.06 mol) inmethanol (1 lit.), thionyl chloride (150.7 g, 1.2 mol) was addeddropwise at 0° C. and then stirred at 65° C. for 12 h. The reactionmixture was concentrated and to the residue dichloromethane and aqueoussodium carbonate solutions were added. The organic layer was dried withsodium sulphate and concentrated to afford the title compound as a brownsolid (150 g, 75%).

Step 3: Quinoline-6-carboxamide

To a solution of methyl quinoline-6-carboxylate (148 g, 0.79 mol) inmethanol (600 ml.), aqueous ammonia (800 ml) was added and then stirredat 45° C. for 12 h. The reaction mixture was concentrated to afford thetitle compound as a dark red solid (120 g, 88%).

Step 4: Quinoline-6-carbonitrile

To a solution of quinoline-6-carboxamide (177 g, 1.03 mol) in chloroform(1.5 lit.) and triethylamine (520.15 g, 5.15 mol), trifluoroaceticanhydride (540.34 g, 2.57 mol) was added dropwise below 10° C. After 1.5h, the pH was adjusted to 7 with sodium bicarbonate solution andextracted with dichloromethane. The organic layer was dried with sodiumsulphate and concentrated to afford the title compound as a brown solid(96 g, 59%).

Step 5: Quinolin-6-ylmethanamine

To a solution of quinoline-6-carbonitrile (96 g, 0.62 mol) in saturatedammonia in methanol (1 lit.), Raney-Ni (10 g) was added and the mixturewas stirred at 1 atm of H₂ at RT for 16 h. The reaction mixture wasfiltered and the filtrate was concentrated under vacuum to afford thetitle compound as a brown oil (80 g, 82%). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 8.83 (dd, J=4.2, 1.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.95 (d,J=8.6 Hz, 1H), 7.85 (s, 1H), 7.75 (dd J=8.7, 1.8 Hz, 1H), 7.49 (dd,J=8.2, 4.2 Hz, 1H), 3.90 (s, 2H).

Intermediate 2: 2-(quinolin-6-yl)propan-2-amine Step 1:2-(quinolin-6-yl)propan-2-ol

To an ice-cold solution of methylmagnesium iodide prepared frommagnesium (0.454 g, 18.69 mmol) and methyliodide (1.16 ml, 18.69 mmol)in diethyl ether (15 ml), methyl quinoline-6-carboxylate (0.50 g, 2.67mmol) in diethyl ether (5 ml) was added and warmed to room temperature.After 12 h, the reaction mixture was cooled to 0° C., quenched with dil.6N HCl and extracted with ethyl acetate. The organic layer was driedover sodium sulphate and concentrated under reduced pressure and columnchromatographed with ethyl acetate: petroleum ether to afford the titlecompound as a yellow liquid (0.42 g, 84%). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.83 (dd J=4.2, 1.7 Hz, 1H), 8.34 (dd, J=8.2, 1.1 Hz, 1H), 8.00(d, J=1.9 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.88 (dd, J=8.9, 2.0 Hz, 1H),7.50 (q, J=4.1 Hz, 1H), 5.23 (s, 1H), 1.51 (s, 6H).

Step 2: 6-(2-azidopropan-2-yl)quinoline

2-(Quinolin-6-yl)propan-2-ol (0.50 g, 2.67 mmol) and sodium azide (1.73g, 26.70 mmol) were added successively to ice-cold trifluoroacetic acid(20 ml) and warmed to room temperature. After 12 h, the reaction mixturewas cooled to 0° C., quenched with water and basified with sodiumhydroxide solution and extracted with ethyl acetate. The organic layerwas dried over sodium sulphate and concentrated under reduced pressureto afford the title compound as brown liquid (0.340 g, 60%). ¹H-NMR (δppm, DMSO-d₆, 400 MHz): δ 8.90 (dd J=4.1, 1.6 Hz, 1H), 8.41 (d, J=7.6Hz, 1H), 8.06 (d, J=2.1 Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.88 (dd,J=8.1, 2.2 Hz, 1H), 7.56 (q, J=4.2 Hz, 1H), 1.71 (s, 6H).

Step 3: 2-(quinolin-6-yl)propan-2-amine

To 6-(2-azidopropan-2-yl)quinoline (0.100 g, 2.67 mmol) in ethanol (3ml), palladium on carbon (10 mg, 10% w/w) was added and stirred under ahydrogen atmosphere using hydrogen filled balloon. After 6 h, thereaction mass was filtered through celite, washed with methanol andconcentrated to afford the title compound as brown liquid (0.079 g,90%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.82 (dd J=4.2, 1.6 Hz, 1H),8.31 (d, J=8.9 Hz, 1H), 8.02 (d, J=1.9 Hz, 1H), 7.99 (dd, J=8.9, 2.1 Hz,1H), 7.93 (d, J=8.9 Hz, 1H), 7.49 (q, J=4.2 Hz, 1H), 2.06 (s, 2H), 1.46(s, 6H).

Intermediate 3: (7-fluoroquinolin-6-yl)methanamine Step 1:6-Bromo-7-fluoroquinoline

To a mixture of 4-bromo-2-fluoroaniline (10 g, 52.62 mmol), ferroussulphate (3.33 g, 11.97 mmol) and glycerol (15.78 ml), con. sulphuricacid (9.15 ml) was added slowly and the reaction mixture was heated to140° C. After 12 h, the reaction mixture was cooled to 0° C. and the pHadjusted to 10-12 with 10% sodium hydroxide solution. The reactionmixture was filtered through celite, washed with ethyl acetate andlayers were separated. The organic layer was washed with brine solution,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with ethyl acetate: petroleum ether toafford the title compound as a white solid (4.9 g, 44%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): 8.96 (dd, J=4.3, 2.7 Hz, 1H), 8.15 (m, 2H), 7.81 (d,J=9.5 Hz, 1H), 7.42 (dd, J=8.3, 4.3 Hz, 1H).

Step 2: 7-Fluoroquinoline-6-carbonitrile

To a solution of 6-bromo-7-fluoroquinoline (4.90 g, 22.12 mmol) indimethylacetamide (38 ml), potassium ferrocyanide (2.65 g, 4.86 mmol)and sodium carbonate (2.34 g, 22.12 mmol). The system was purged withnitrogen for 15 min. Palladium acetate (0.248 g, 1.10 mmol) was addedunder nitrogen and heated to 120° C. After 3 h, the reaction mixture wasfiltered through celite, washed with ethyl acetate. The organic layerwas washed with brine solution, dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith ethyl acetate: petroleum ether to afford the title compound as awhite solid (3.2 g, 86%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 9.05 (dd,J=4.1, 2.9 Hz, 1H), 8.25 (m, 2H), 7.90 (d, J=10.0 Hz, 1H), 7.53 (dd,J=8.3, 4.3 Hz, 1H).

Step 3: (7-Fluoroquinolin-6-yl) methanamine

To 7-fluoroquinoline-6-carbonitrile (1.00 g, 5.813 mmol), methanolsaturated with ammonia (13.5 ml) and Raney-Ni (1.27 g) were added andhydrogenated at 50-60 psi for 4 h. The reaction mixture was filtered andconcentrated to afford the title compound as a brown oil (0.80 g, 78%).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.85 (d, J=2.3 Hz, 1H), 8.35 (d, J=8.0Hz, 1H), 8.06 (d, J=9.5 Hz, 1H), 7.68 (d, J=11.8 Hz, 1H), 7.49 (t, J=3.8Hz, 1H), 3.92 (s, 2H), 1.90 (br s, 2H).

Intermediate 4: 6-Chloro-3-nitro-N-(quinolin-6-ylmethyl)pyridin-2-amine

To a solution of 2,6-Dichloro-3-nitropyridine (1.62 g, 8.42 mmol) inethanol (30 ml), sodium carbonate (2.34 g, 22.12 mmol) was added at RTand cooled to 0° C. followed by the addition of intermediate 1 (2 g,12.64 mmol) in ethanol (20 ml) the mixture was stirred at RT for 12 h.The reaction mixture was poured into 25 ml of water and extracted withethyl acetate, washed with brine solution, dried over sodium sulphateand concentrated. The crude product was purified by columnchromatography with dichloromethane:methanol to afford the titlecompound as a yellow solid (2.0 g, 50%). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 9.35 (t, J=6.0 Hz, 1H), 8.85 (dd, J=4.0, 1.4 Hz, 1H), 8.46 (d,J=8.5 Hz, 1H), 8.31 (d, J=7.8 Hz, 1H), 7.98 (d J=8.7 Hz, 1H), 7.88 (s,1H), 7.79 (dd, J=8.7, 1.6 Hz, 1H), 7.50 (dd, J=8.3, 4.2 Hz, 1H), 6.80(d, J=8.6 Hz, 1H), 4.92 (d, J=6.1 Hz, 2H).

Intermediate 5: 6-chloro-N-(4-fluorobenzyl)-3-nitropyridin-2-amine

The title compound was obtained as a yellow solid (2.1 g, 70%) by usinga procedure that is similar to the one described for intermediate 4 from2,6-Dichloro-3-nitropyridine (2.05 g, 10.65 mmol), 4-Fluorobenzylamine(2.0 g, 15.98 mmol), ethanol (50 ml) and sodium carbonate (2.94 g, 27.80mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 9.21 (t, J=5.9 Hz, 1H), 8.43(d, J=8.6 Hz, 1H), 7.43 (m, 2H), 7.15 (m, 2H), 6.79 (d, J=8.6 Hz, 1H),4.68 (d, J=6.1 Hz, 2H).

Intermediate 6: 6-chloro-N-(2-chloro-3,6-difluorobenzyl)-3-nitropyridin2-amine

The title compound was obtained as a yellow solid (1.14 g, 61%) by usinga procedure that is similar to the one described for intermediate 4 from2,6-Dichloro-3-nitropyridine (0.724 g, 3.75 mmol),2-chloro-3,6-difluorobenzylamine (1.0 g, 5.63 mmol), ethanol (25 ml) andsodium carbonate (2.94 g, 27.80 mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.94 (t, J=5.5 Hz, 1H), 8.41 (d, J=8.6 Hz, 1H), 7.44 (dt, J=9.0, 4.7Hz, 1H), 7.34 (dt, J=9.3, 4.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 4.86 (d,J=5.5 Hz, 2H).

Intermediate 7:6-chloro-3-nitro-N-(2-(quinolin-6-yl)propan-2-yl)pyridin-2-amine

The title compound was obtained as a yellow solid (0.860 g, 47%) byusing a procedure that is similar to the one described for intermediate4 from 2,6-Dichloro-3-nitropyridine (1.55 g, 8.05 mmol), Intermediate 2(1.0 g, 5.36 mmol), ethanol (35 ml) and sodium carbonate (2.34 g, 22.12mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.84 (dd, J=4.2, 1.7 Hz, 1H),8.76 (s, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.33 (d, J=7.3 Hz, 1H), 8.00 (d,J=1.9 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.85 (dd, J=8.9, 2.1 Hz, 1H),7.49 (q, J=4.2 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 1.89 (s, 6H).

Intermediate 8:6-Chloro-N-((7-fluoroquinolin-6-yl)methyl)-3-nitropyridin-2-amine

The title compound was obtained as a yellow solid (0.750 g, 50%) byusing a procedure that is similar to the one described for intermediate4 from 2,6-dichloro-3-nitropyridine (1.31 g, 6.81 mmol), Intermediate 3(0.80 g, 4.54 mmol), ethanol (15 ml) and sodium carbonate (0.838 g, 7.90mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.27 (t, J=5.7 Hz, 1H), 8.87(d, J=2.8 Hz, 1H), 8.49 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.96(d, J=8.4 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.49 (dd, J=8.3, 4.2 Hz, 1H),6.83 (d, J=8.6 Hz, 1H), 4.95 (d, J=5.9 Hz, 2H).

Intermediate 9: 6-chloro-N2-(quinolin-6-ylmethyl) pyridine-2,3-diamine

Stannous chloride (0.258 g, 1.143 mmol) and conc. HCl (3 ml) were addedto intermediate 4 (0.180 g, 0.571 mmol) at RT and stirred for 1 h. After1 h stannous chloride (0.258 g, 1.143 mmol) and conc. HCl (2 ml) wereadded and maintained for 1 h. The reaction mixture was poured into icewater and the pH was adjusted to ca. (approx) 8 with sodium bicarbonatesolution, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulphate and concentrated to afford the title compoundas a yellow solid (0.150 g, 92%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ8.85 (dd, J=4.2, 1.6 Hz, 1H), 8.32 (d, J=7.9 Hz, 1H), 7.98 (d, J=8.7 Hz,1H), 7.86 (s, 1H), 7.76 (dd, J=8.7, 1.8 Hz, 1H), 7.51 (dd, J=8.3, 4.2Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.59 (t, J=5.6 Hz, 1H), 6.38 (d, J=7.7Hz, 1H), 4.92 (s, 2H), 4.70 (s, 2H).

Intermediate 10: 6-chloro-N2-(4-fluorobenzyl)pyridine-2,3-diamine

The title compound was obtained as a yellow solid (1.3 g, 99%) by usinga procedure that is similar to the one described for intermediate 9 fromintermediate 5 (1.5 g, 5.33 mmol), stannous chloride (4.09 g, 18.13mmol) and conc. HCl (11.5 ml). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.38(m, 2H), 7.15 (m, 2H), 6.71 (d, J=7.8 Hz, 1H), 6.43 (t, J=5.9 Hz, 1H),6.37 (d, J=7.8 Hz, 1H), 4.87 (s, 2H), 4.47 (d, J=5.6 Hz, 2H).

Intermediate 11:6-chloro-N2-(2-chloro-3,6-difluorobenzyl)pyridine-2,3-diamine

Iron powder (2.0 g, 35.81 mmol) was added to a solution of theintermediate 6 (1.0 g, 2.99 mmol) in methanol (10 ml) and conc. HCl (1.5ml) were added at RT and refluxed for 5 h. The reaction mixture wasfiltered through celite and concentrated. Ice water was added to theresidue and the pH was adjusted to ca. 8 with sodium bicarbonatesolution, extracted with ethyl acetate, washed with brine, dried overanhydrous sodium sulphate and concentrated to afford the title compoundas a yellow solid (0.67 g, 74%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ7.47 (dt, J=9.0, 4.8 Hz, 1H), 7.34 (dt, J=9.1, 4.3 Hz, 1H), 6.69 (d,J=7.7 Hz, 1H), 6.40 (d, J=7.7 Hz, 1H), 6.13 (t, J=4.4 Hz, 1H), 4.89 (s,2H), 4.55 (d J=3.5 Hz, 2H).

Intermediate 12:6-chloro-N2-(2-(quinolin-6-yl)propan-2-yl)pyridine-2,3-diamine

Acetic acid (30 ml) was added at RT to a mixture of intermediate 7 (2.0g, 5.83 mmol) and iron powder (1.6 g, 29.17 mmol) and stirred for 12 h.The reaction mixture was basified with sodium bicarbonate solution,extracted with ethyl acetate, washed with brine, dried over anhydroussodium sulphate and concentrated to afford the title compound as a brownsolid (1.42 g, 77%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.80 (d, J=2.7Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.92 (s, 1H), 7.89 (d, J=8.0 Hz, 1H),7.76 (d, J=8.8 Hz, 1H), 7.46 (q, J=4.2 Hz, 1H), 6.66 (d, J=7.7 Hz, 1H),6.20 (d, J=7.7 Hz, 1H), 6.04 (s, 1H), 5.02 (s, 2H), 1.79 (s, 6H).

Intermediate 13:6-Chloro-N2-((7-fluoroquinolin-6-yl)methyl)pyridine-2,3-diamine

The title compound was obtained as a yellow solid (0.550 g, 74%) byusing a procedure that is similar to the one described for intermediate9 from intermediate 8 (0.750 g, 2.25 mmol), stannous chloride (2.28 g,10.14 mmol) and conc. HCl (13 ml). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ8.87 (d, J=3.0 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 7.97 (d, J=8.3 Hz, 1H),7.77 (d, J=11.6 Hz, 1H), 7.50 (dd, J=8.2, 4.1 Hz, 1H), 6.74 (d, J=8.5Hz, 1H), 6.54 (t, J=5.0 Hz, 1H), 6.39 (d, J=7.8 Hz, 1H), 4.94 (s, 2H),4.72 (d, J=5.3 Hz, 2H).

Intermediate 14:6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

Intermediate 9 (0.220 g, 0.772 mmol) was dissolved in acetic acid (1.3ml) and cooled to 5° C. Sodium nitrite (0.063 g, 0.927 mmol) in 0.35 mlwater was added slowly followed by sulphuric acid (0.09 ml). Thereaction mixture was warmed to RT and stirred for 30 min. The reactionmixture was poured into ice water and pH adjusted to ca. 8 with sodiumbicarbonate solution, extracted with ethyl acetate, washed with brine,dried over sodium sulphate and concentrated to afford the title compoundas a brown solid (0.220 g, 96%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ8.88 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.01 (d,J=8.6 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.61 (d, J=8.5 Hz,1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 6.12 (s, 2H).

Intermediate 15:5-chloro-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridine

The title compound was obtained as a brown solid (1.0 g, 76%) by using aprocedure that is similar to the one described for intermediate 14 fromintermediate 10 (1.3 g, 5.17 mmol), acetic acid (9 ml), sodium nitrite(0.428 g, 6.20 mmol), water (2.4 ml) and sulphuric acid (0.58 ml).¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.66 (d, J=8.7 Hz, 1H), 7.60 (d,J=8.6 Hz, 1H), 7.43 (m, 2H), 7.20 (m, 2H), 5.90 (s, 2H).

Intermediate 16:5-chloro-3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridine

The title compound was obtained as a brown solid (0.66 g, 98%) by usinga procedure that is similar to the one described for intermediate 14from intermediate 11 (0.65 g, 2.13 mmol), acetic acid (4 ml), sodiumnitrite (0.177 g, 2.56 mmol), water (0.93 ml) and sulphuric acid (0.58ml). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.66 (d, J=8.7 Hz, 1H), 7.61(d, J=8.8 Hz, 1H), 7.60 (dt, J=9.0, 4.9 Hz, 1H), 7.45 (dt, J=9.2, 4.2Hz, 1H), 5.98 (s, 2H).

Intermediate 17:6-(2-(5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)quinoline

The title compound was obtained as a brown solid (1.1 g, 91%) by using aprocedure that is similar to the one described for intermediate 14 fromintermediate 12 (1.20 g, 3.83 mmol), acetic acid (7.2 ml), sodiumnitrite (0.317 g, 4.604 mmol), water (2.8 ml) and sulphuric acid (0.5ml). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.88 (dd, J=4.2, 1.5 Hz, 1H),8.29 (d, J=8.6 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.10 (d, J=8.9 Hz, 1H),7.70 (d, J=2.1 Hz, 1H), 7.48 (dd, J=8.9, 2.2 Hz, 1H), 7.41 (q, J=4.2 Hz,1H), 7.25 (m, 1H), 2.44 (s, 6H). Mass: 323.76 (M⁺).

Intermediate 18:6-((5-Chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-7-fluoroquinoline

The title compound was obtained as a brown solid (0.345 g, 62%) by usinga procedure that is similar to the one described for intermediate 14from intermediate 13 (0.540 g, 1.78 mmol), acetic acid (3.1 ml), sodiumnitrite (0.148 g, 2.13 mmol), water (0.8 ml) and sulphuric acid (0.2ml). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.91 (d, J=2.9 Hz, 1H), 8.36 (d,J=8.6 Hz, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.80 (d, J=11.0 Hz, 1H), 7.70 (d,J=7.8 Hz, 1H), 7.40 (m, 2H), 6.11 (s, 2H).

Intermediate 19:2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol Step 1: 1-(4-bromo-2-fluorophenyl)ethanol

A solution of 4-bromo-2-fluorobenzaldehyde (5 g, 24.62 mmol) in diethylether (10 ml) was added to an ice-cold solution of methylmagnesiumiodide prepared from magnesium (1.7 g, 73.88 mmol) and methyliodide(4.58 ml, 73.88 mmol) in diethyl ether (50 ml). The mixture was warmedstirred at RT. for 12 h, and cooled to 0° C., quenched with dil. 6N HCland extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated under reduced pressure to afford thetitle compound as red colour liquid (5 g, 94%). ¹H-NMR (δ ppm, CDCl₃,400 MHz): δ 7.40 (t, J=8.2 Hz, 1H), 7.30 (dd, J=8.3, 1.7 Hz, 1H), 7.21(dd, J=9.9, 1.9 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).

Step 2: 1-(4-bromo-2-fluorophenyl)ethanone

To a solution of intermediate 19 (step 1) (5.0 g, 22.82 mmol) in DMF (25ml), pyridinium dichromate (12.8 g, 34.23 mmol) was added at roomtemperature. After 12 h, the reaction mixture was quenched with water,diluted with ethyl acetate and filtered through celite. The organiclayer was washed with brine solution and dried over sodium sulphate andconcentrated under reduced pressure to afford the title compound as ared colour liquid (4.1 g, 84%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 7.76(t, J=8.3 Hz, 1H), 7.73 (dd, J=10.8, 1.8 Hz, 1H), 7.55 (dd, J=5.2, 1.8Hz, 1H), 2.55 (s, 3H).

Step 3: 2-(4-bromo-2-fluorophenyl)propan-2-ol

A procedure similar to the one described in step 1 was followed to getthe crude product from magnesium (0.33 g, 73.88 mmol), methyliodide(0.856 ml, 13.69 mmol), diethyl ether (10 ml) and the intermediate fromstep 2 (1 g, 4.56 mmol) in diethyl ether (10 ml). Purification by columnchromatography with ethyl acetate: petroleum ether gave the titlecompound as a yellow liquid (0.5 g, 47% yield). ¹H-NMR (δ ppm, CDCl₃,400 MHz): δ 7.48 (t, J=8.6 Hz, 1H), 7.27 (m, 1H), 7.21 (dd, J=11.3, 1.9Hz, 1H), 2.04 (s, 1H), 1.60 (s, 6H).

Step 4:2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol

Potassium acetate (0.404 g, 4.11 mmol) and bis(pinacolato)diboron (0.575g, 2.26 mmol) were added to a solution of the intermediate from step 3(0.4800 g, 2.05 mmol) in dioxane (16 ml), and the solution was degassedfor 30 min. [1,1′-bis (diphenylphosphino) ferrocene]dichloropalladium(II).CH₂Cl₂ (0.084 g, 0.102 mmol) was added under nitrogenatmosphere and heated to 80° C. After 12 h, the reaction mixture wasfiltered through celite and concentrated. The crude product was purifiedby column chromatography with ethyl acetate: petroleum ether to affordthe title compound as a colourless oil (0.450 g, 61%). ¹H-NMR (δ ppm,CDCl₃, 400 MHz): δ 7.55 (s, 1H), 7.54 (d, J=4.8 Hz, 1H), 7.46 (d, J=12.6Hz, 1H), 2.13 (d, J=3.5 Hz, 1H), 1.63 (d, J=5.5 Hz, 6H), 1.33 (s, 12H).

Intermediate 20:2-(3-fluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneStep 1: 4-bromo-2-fluoro-1-isopropoxybenzene

To a solution of 4-bromo-3-fluorophenol (10 g, 52.35 mmol) in THF (100ml), isopropyl alcohol (4.8 ml, 62.62 mmol) and triphenylphosphine (20.6g, 78.52 mmol) were added and heated to 45° C. followed bydiisopropylazodicarboxylate (15.4 ml, 78.52 mmol). The mixture wasrefluxed for 1 h, concentrated and the residue was purified by columnchromatography with ethyl acetate: petroleum ether to afford the titlecompound as a colourless liquid (13.1 g, 99%) which was used withoutpurification in the next step.

Step 2:2-(3-fluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was obtained as a yellow oil (13.9 g, 99%) by usingthe procedure described in step 4 for intermediate 19 from the productof step 1 (12.5 g g, 53.60 mmol), bis(pinacolato)diboron (15 g, 58.96mmol), potassium acetate (10.52 g, 107.2 mmol), dioxane (125 ml) and[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II). CH₂Cl₂(4.4 g, 5.36 mmol) which was used without purification in the next step.

Intermediate 21:2-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

The title compound was obtained as a brown solid (0.600 g, 70%) by usingthe procedure described in step 4 for intermediate 19 from4-bromo-2-methylbenzamide (0.700 g, 3.27 mmol), bis(pinacolato)diboron(0.913 g, 3.59 mmol), potassium acetate (0.96 g, 9.81 mmol), dioxane (12ml) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.080 g, 0.098 mmol) which was used withoutcharacterisation in the next step.

Intermediate 22:2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

The title compound was obtained as a brown solid (0.75 g, 69%) by usingthe procedure described in step 4 for intermediate 19 from5-bromo-2-chlorobenzamide (0.800 g, 3.83 mmol), bis(pinacolato)diboron(1.07 g, 4.21 mmol), potassium acetate (1.12 g, 11.49 mmol), dioxane(10.5 ml) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.083 g, 0.102 mmol) which was used withoutcharacterisation in the next step.

Intermediate 23: 3-amino-N,N-dimethylpropanamide trifluoroacetate

To a solution of N-boc-3-aminopropanoic acid (0.150 g, 0.793 mmol) inDMF (1.5 ml), N-Ethyldiisopropylamine (0.205 g, 1.58 mmol) and HATU(0.301 g, 0.793 mmol) were added and stirred for 5 min. Dimethylaminehydrochloride (0.065 g, 0.793 mmol) was added at RT and the reactionmixture was stirred for 12 h. Water was added to the reaction mixtureand extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to affordtert-butyl 3-(dimethylamino)-3-oxopropylcarbamate. Trifluoroacetic acid(1 ml) was added to the product obtained, stirred for 2 h andconcentrated to afford title compound as the trifluoroacetate salt(0.090 g, 40%).

Intermediate 24: 2-amino-N,N-dimethylacetamide trifluoroacetate

Tert-butyl 2-(dimethylamino)-2-oxoethylcarbamate (0.120 g, 69%) wasobtained by using the procedure described under intermediate 23 fromN-boc-glycine (0.150 g, 0.856 mmol), DMF (1.5 ml),N-Ethyldiisopropylamine (0.221 g, 1.70 mmol), HATU (0.325 g, 0.856 mmol)and dimethylamine hydrochloride (0.069 g, 0.856 mmol). The product wasdissolved in dichloromethane (1 ml), trifluoroacetic acid (0.5 ml) wasadded, stirred for 2 h and concentrated to give the title compound asthe trifluoroacetate salt (0.100 g, 46%).

Intermediate 25: 2-amino-1-(pyrrolidin-1-yl)ethanone trifluoroacetate

Tert-butyl 2-oxo-2-(pyrrolidin-1-yl)ethylcarbamate (0.120 g, 61%) wasprepared by using the procedure described under intermediate 23 fromN-boc-glycine (0.150 g, 0.856 mmol), DMF (1.5 ml),N-Ethyldiisopropylamine (0.110 g, 0.856 mmol), HATU (0.325 g, 0.856mmol) and pyrrolidine (0.061 g, 0.856 mmol). The product was dissolvedin dichloromethane (1 ml), trifluoroacetic acid (0.5 ml) was added,stirred for 2 h and concentrated to give the title compound as thetrifluoroacetate salt (0.100 g, 41%).

Intermediate 26: 3-amino-1-(pyrrolidin-1-yl)propan-1-onetrifluoroacetate

Tert-butyl 2-oxo-2-(pyrrolidin-1-yl)propylcarbamate (0.080 g, 40%) wasprepared by using the procedure described under intermediate 23 fromN-boc-3-aminopropionic acid (0.150 g, 0.793 mmol), DMF (1.5 ml),N-Ethyldiisopropylamine (0.205 g, 1.58 mmol), HATU (0.301 g, 0.793 mmol)and pyrrolidine (0.056 g, 0.793 mmol). Trifluoroacetic acid (1 ml) wasadded to the product, stirred for 2 h and concentrated to give the titlecompound as the trifluoroacetate salt (0.080 g, 40%).

Intermediate 27: 3-amino-1-(piperidin-1-yl)propan-1-one trifluoroacetate

Tert-butyl 2-oxo-2-(piperidin-1-yl)propylcarbamate was prepared by usingthe procedure described under intermediate 23 fromN-boc-3-aminopropionic acid (0.250 g, 1.32 mmol), DMF (2.5 ml),N-Ethyldiisopropylamine (0.171 g, 1.32 mmol), HATU (0.503 g, 1.32 mmol)and piperidine (0.225 g, 2.64 mmol). Trifluoroacetic acid (1 ml) wasadded to the product, stirred for 2 h and concentrated to give the titlecompound as the trifluoroacetate salt (0.120 g, 34%).

Intermediate 28: 3-amino-1-morpholinopropan-1-one trifluoroacetate

Tert-butyl 3-morpholino-3-oxopropylcarbamate was prepared by using theprocedure described under intermediate 23 from N-boc-3-aminopropionicacid (0.250 g, 1.32 mmol), DMF (2.5 ml), N-Ethyldiisopropylamine (0.171g, 1.32 mmol) and HATU (0.503 g, 1.32 mmol) and morpholine (0.230 g,2.64 mmol). Trifluoroacetic acid (1 ml) was added to the product,stirred for 2 h and concentrated to give the title compound as thetrifluoroacetate salt (0.120 g, 33%).

Intermediate 29:6-((5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline

Intermediate 9 (0.200 g, 0.702 mmol) was dissolved in formic acid (1.0ml) and heated to 100° C. and stirred for 12 h. The reaction mixture waspoured into ice water and pH adjusted to 7-8 with sodium bicarbonatesolution, extracted with ethyl acetate, washed with brine, dried oversodium sulphate and concentrated to afford the title compound asyellowish brown solid (0.200 g, 97% yield). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 8.88 (dd, J=4.0, 1.3 Hz, 1H), 8.70 (s, 1H), 8.33 (d, J=8.2 Hz,1H), 8.19 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.73(dd, J=8.7, 1.7 Hz, 1H), 7.52 (dd, J=8.3, 2.2 Hz, 1H), 7.37 (d, J=8.4Hz, 1H), 5.69 (s, 2H).

Intermediate 30:6-chloro-3-nitro-N-(1-(quinolin-6-yl)ethyl)pyridin-2-amine

The title compound was obtained as a yellow solid (0.785 g, 50%) byusing a procedure that is similar to the one described for intermediate4 from 2,6-Dichloro-3-nitropyridine (0.924 g, 4.78 mmol),1-(quinolin-6-yl)ethanamine (1.25. g, 7.25 mmol), ethanol (7 ml) andsodium carbonate (1.32 g, 12.54 mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):δ 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.78 (d, J=7.5 Hz, 1H), 8.44 (d, J=8.6Hz, 1H), 8.33 (dd, J=8.3, 1.0 Hz, 1H), 7.99 (m, 2H), 7.89 (dd, J=8.8,1.9 Hz, 1H), 7.51 (q, J=4.2 Hz, 1H), 6.80 (d, J=7.5 Hz, 1H), 5.57(quintet, J=7.1 Hz, 1H). 1.69 (d, J=7.0 Hz, 3H).

Intermediate 31:6-(1H-pyrazol-4-yl)-N2-(1-(quinolin-6-yl)ethyl)pyridine-2,3-diamine

To a solution of intermediate 30 (0.20 g, 0.608 mmol) and1-tert-butoxycarbonyl-1H-pyrazole-4-boronic acid pinacol ester (0.229 g,0.778 mmol) in dioxane (4 ml), potassium carbonate (0.279 g, 2.02 mmol)and water (0.8 ml) were added and degassed for 30 min.Tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.047 mmol) was addedunder nitrogen at RT and the reaction mixture was refluxed for 12 h. Thesolvent was evaporated completely and to the residue water was added andextracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure to afford the crude pyrazolecompound as a yellow solid (0.219 g). To a solution of this intermediatein conc. HCl (3 ml), stannous chloride (0.750 g, 18.13 mmol) was addedat RT and stirred for 5 h. The reaction mixture was poured into icewater and pH adjusted to 7-8 with sodium bicarbonate solution, extractedwith ethyl acetate, washed with brine, dried over anhydrous sodiumsulphate and concentrated to afford the title compound as yellow solid(0.194 g, 97%) which was used as such for the next step.

Intermediate 32:6-chloro-N-((5,7-difluoroquinolin-6-yl)methyl)-3-nitropyridin-2-amineStep 1: 2-(5,7-difluoroquinolin-6-yl)acetic acid

A mixture of 4-amino-2,6-difluorophenylacetic acid (3.2 g, 17.1 mmol),ferrous sulphate (1.04 g, 3.76 mmol), nitrobenzene (1.05 ml, 10.26 mmol)and conc. H₂SO₄ in glycerol (5.2 ml) was heated at 150° C. for 16 h. Themixture was cooled to RT, methanol (28 ml) was added followed by aq. 6NNaOH (28 ml) and heated at 110° C. for 3 h. After cooling to RT, themixture was acidified with conc. HCl to pH 3.0. The precipitate formedwas filtered, washed with water and dried under vacuum. The precipitatewas refluxed with methanol, filtered under hot conditions and thefiltrate was evaporated to give the title compound (1 g, 25%) as a brownsolid. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 12.72 (bs, 1H), 8.98 (d,J=3.1 Hz, 1H); 8.47 (d, J=8.4, 1H); 7.71 (d, J=9.7, 1H); 7.62 (dd,J=8.4, 4.1, 2H); 3.85 (s, 2H).

Step 2: (5,7-difluoroquinolin-6-yl)methanamine

Diphenyl phosphoryl azide (0.5 ml, 2.32 mmol), triethylamine (0.34 ml,2.43 mmol) and tert-butanol (1.3 ml, 13.78 mmol) were added to asolution of the product from step 1 (0.5 g, 2.24 mmol) in dioxan (6.5ml) and heated at 110° C. for 4 h. The mixture was cooled to RT anddistributed between ethyl acetate and aq. 10% citric acid. The organiclayer was separated, dried over Na₂SO₄ and concentrated to leave a brownresidue which was dissolved in dioxane (5 ml) and dichloromethane (1.5ml) and treated with ether saturated with HCl (10 ml) and stirred at RTovernight. After removing the solvents completely, aq. NaHCO₃ was addedto the residue and extracted into ethyl acetate, the organic layer driedover Na₂SO₄ and the solvent was removed. Purification of the residue bycolumn chromatography gave the title compound as a mixture containingca. 35 mol % of 1,3-bis((5,7-difluoroquinolin-6-yl)methyl)urea, whichwas used as such in the next step. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ8.95 (d, J=3.8 Hz, 2H); 8.45 (dd, J=7.5, 5.2, 2H); 7.65 (d, J=10.9, 2H);7.59 (dd, J=8.29, 4.2, 2H); 6.50 (t, J=5.6, 1H), 4.44 (d, J=5.6, 2H);3.90 (s, 2H).

Step 3:6-chloro-N-((5,7-difluoroquinolin-6-yl)methyl)-3-nitropyridin-2-amine

The title compound was obtained as a yellow solid (0.050 g, 5%) by usinga procedure that is similar to the one described for intermediate 4 from2,6-Dichloro-3-nitropyridine (1.40 g, 7.73 mmol),(5,7-difluoroquinolin-6-yl)methanamine (1.00 g, 5.15 mmol), ethanol (10ml) and sodium carbonate (0.97 g, 9.22 mmol). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): δ 9.09 (t, J=5.1 Hz, 1H), 8.96 (d, J=3.7 Hz, 1H), 8.49 (d,J=8.4 Hz, 1H), 8.41 (d, J=8.5 Hz, 1H), 7.68 (d, J=11.0 Hz, 1H), 7.61(dd, J=8.4, 4.2 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 4.97 (d, J=5.5 Hz, 2H).

Intermediate 33:6-chloro-N2-((5,7-difluoroquinolin-6-yl)methyl)pyridine-2,3-diamine

The title compound was obtained as a brown solid (0.080 g, 73%) by usinga procedure that is similar to the one described for intermediate 9 fromintermediate 32 (0.12 g, 0.342 mmol), stannous chloride (0.347 g, 1.54mmol) and conc. HCl (2 ml) which was used as such for the next step.

Intermediate 34:6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)-5,7-difluoroquinoline

The title compound was obtained as a brown solid (0.068 g, 83%) by usinga procedure that is similar to the one described for intermediate 14from intermediate 33 (0.080 g, 0.249 mmol), acetic acid (0.4 ml), sodiumnitrite (0.020 g, 0.299 mmol), water (0.2 ml) and sulphuric acid (0.1ml). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.98 (d, J=2.7 Hz, 1H), 8.43 (d,J=8.2 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 7.65 (d, J=10.4 Hz, 1H), 7.48(dd, J=8.5, 4.3 Hz, 1H), 6.10 (s, 2H), 7.39 (d, J=8.6 Hz, 1H).

Intermediate 35:2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

The title compound was obtained as a brown solid (0.75 g, 69%) by usingthe procedure described in step 4 for intermediate 19 from4-bromo-2-chlorobenzamide (0.500 g, 2.13 mmol), bis(pinacolato)diboron(0.595 g, 2.34 mmol), potassium acetate (0.627 g, 6.39 mmol), dioxane(3.6 ml) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).CH₂Cl₂ (0.052 g, 0.063 mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): δ 7.91 (s, 1H), 7.89 (m, 1H), 7.61 (m, 2H), 7.44 (d, J=7.6 Hz,1H), 1.14 (s, 12H).

Intermediate 36:N-(benzo[d]thiazol-6-ylmethyl)-6-chloro-3-nitropyridin-2-amine

The title compound was obtained as a yellow solid (0.460 g, 9%) by usinga procedure that is similar to the one described for intermediate 4 from2,6-Dichloro-3-nitropyridine (4.75 g, 24.66 mmol),benzo[d]thiazol-6-ylmethanamine (2.70 g, 16.44 mmol), ethanol (50 ml)and sodium carbonate (3.03 g, 28.60 mmol) which was used as such for thenext step.

Intermediate 37:N2-(benzo[d]thiazol-6-ylmethyl)-6-chloropyridine-2,3-diamine

The title compound was obtained as a yellow solid (0.360 g, 88%) byusing a procedure that is similar to the one described for intermediate9 from intermediate 36 (0.450 g, 1.40 mmol), stannous chloride (1.42 g,6.31 mmol) and conc. HCl (7.5 ml) which was used as such for the nextstep.

Intermediate 38:6-((5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole

The title compound was obtained as a brown solid (0.068 g, 83%) by usinga procedure that is similar to the one described for intermediate 14from intermediate 37 (0.350 g, 0.249 mmol), acetic acid (1.75 ml),sodium nitrite (0.099 g, 1.44 mmol), water (0.8 ml) and sulphuric acid(0.4 ml). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.99 (s, 1H), 8.32 (d, J=8.5Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 7.66 (d, J=8.4 Hz, 1H),7.36 (d, J=8.5 Hz, 1H), 6.00 (s, 2H).

Intermediate 39:6-chloro-N2-(1-(quinolin-6-yl)ethyl)pyridine-2,3-diamine

The title compound was obtained as a pale brown solid (0.600 g, 74%) byusing a procedure that is similar to the one described for intermediate9 from intermediate 30 (0.900 g, 2.72 mmol), stannous chloride (2.77 g,12.28 mmol) and conc.HCl (1.5 ml) which is used without purification fornext step.

Intermediate 40:6-(1-(5-chloro-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline

The title compound was obtained as a brown solid (0.500 g, 84%) by usinga procedure that is similar to the one described for intermediate 14from intermediate 39 (0.575 g, 1.91 mmol), acetic acid (3.5 ml), sodiumnitrite (0.159 g, 2.30 mmol), water (1 ml) and sulphuric acid (0.3 ml).¹H-NMR (δ ppm, CDCl₃, 400 MHz): δ 8.90 (dd, J=4.0, 2.7 Hz, 1H), 8.31 (d,J=8.6 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 7.93 (s,1H),), 7.89 (dd, J=8.8, 1.9 Hz, 1H), 7.42 (dd, J=8.3, 4.1 Hz, 1H), 7.34(d, J=8.6 Hz, 1H), 6.50 (q, J=7.1 Hz, 1H), 2.29 (d, J=7.2 Hz, 3H).

Intermediate 41: 4-bromo-2-(trifluoromethyl)benzamide

Thionyl chloride (10 ml) was added to 4-bromo-3-(trifluoromethyl)benzoicacid (1.0 g, 3.71 mmol, prepared as described by Hattori et. al. inBioorg. Med. Chem. 2007, 15, 2198,) and refluxed for 3 h. Excess thionylchloride was removed under reduced pressure and the residue was cooledto 0° C. Aqueous 25% ammonia (7 ml) was added and stirred for 15 min.The precipitate formed was washed with sodium bicarbonate solution andvacuum dried to afford title compound as a brown solid (0.500 g, 50%)which is used as such for next step.

Intermediate 42:4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide

The title compound was obtained as a brown solid (0.30 g, 50%) by usingthe procedure described in step 4 for intermediate 19 from intermediate41 (0.500 g, 1.86 mmol), bis(pinacolato)diboron (0.705 g, 2.77 mmol),potassium acetate (0.743 g, 7.57 mmol), dioxane (4.6 ml) and[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II).CH₂Cl₂(0.061 g, 0.067 mmol) which was used without purification for the nextstep.

EXAMPLES Example 16-((5-(4-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of intermediate 14 (0.120 g, 0.405 mmol) and4-methoxyphenylboronic acid (0.078 g, 0.519 mmol) in dioxane (2.4 ml),potassium carbonate (0.186 g, 1.35 mmol) and water (0.5 ml) were addedand degassed for 30 min. tetrakis(triphenylphosphine) palladium(0)(0.037 g, 0.032 mmol) was added under nitrogen at RT and the reactionmixture was refluxed for 12 h. The solvent was evaporated completely andwater was added to the residue and extracted with ethyl acetate, driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.084 g,56%). M.P.: 144-146° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (d, J=2.6Hz, 1H), 8.58 (d, J=8.7 Hz, 1H), 8.37 (d, J=8.1 Hz, 1H), 8.22 (d, J=8.9Hz, 2H), 8.06 (d, J=8.7 Hz, 1H), 8.02 (m, 2H), 7.83 (dd, J=8.8, 1.5 Hz,1H), 7.55 (dd, J=8.4, 4.2 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H), 6.18 (s, 2H),3.83 (s, 3H). MS (m/z): 367.95 (M⁺).

Example 26-((5-(3-Methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.120 g, 0.405 mmol),3-methoxyphenylboronic acid (0.078 g, 0.519 mmol), potassium carbonate(0.186 g, 1.35 mmol), dioxane (2.4 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.037 g, 0.032 mmol). Yellowsolid (0.080 g, 53%). M.P.: 133-135° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.88 (dd, J=4.0, 1.1 Hz, 1H), 8.64 (d, J=8.9 Hz, 1H), 8.36 (d,J=8.4 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 8.02 (s, 1H), 7.99 (d, J=10.2 Hz,1H), 7.83 (m, 2H), 7.74 (s, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.47 (t,J=8.0 Hz, 1H), 7.10 (dd, J=8.2, 2.4 Hz, 1H), 6.21 (s, 2H), 3.83 (s, 3H).MS (m/z): 368.02 (M⁺).

Example 33-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.140 g, 0.473 mmol),3-formylphenylboronic acid (0.098 g, 0.605 mmol), potassium carbonate(0.217 g, 1.57 mmol), dioxane (2.8 ml), water (0.6 ml) andTetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.032 mmol) to givethe title compound quantitatively.

Example 4(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol

Sodium borohydride (0.018 g, 0.493 mmol) was added to a solution ofexample 3 (0.180 g, 0.493 mmol) in methanol (4 ml), cooled to 0° C., andstirred for 1 h. Ice-cold water was added to the mixture, extracted withethyl acetate, washed with brine, dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as a yellowsolid (0.044 g, 24%). M.P. 191-193° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.3 Hz,1H), 8.21 (d, J=8.3 Hz, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 8.02(d, J=8.8 Hz, 1H), 7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (m, 3H), 6.20 (s,2H), 5.30 (t, J=5.7 Hz, 1H), 4.58 (d, J=5.4 Hz, 2H). MS (m/z): 368.37(M⁺+1).

Example 54-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.140 g, 0.473 mmol),4-formylphenylboronic acid (0.098 g, 0.605 mmol), potassium carbonate(0.217 g, 1.57 mmol), dioxane (2.8 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.043 g, 0.037 mmol). Brownsolid (0.100 g, 58%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.10 (s, 1H),8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.48 (d, J=8.3 Hz,2H), 8.39 (dd, J=8.4, 1.0 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.08 (d,J=8.5 Hz, 2H), 8.04 (d, J=1.7 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.84 (dd,J=8.7, 2.0 Hz, 1H), 7.51 (q, J=4.3 Hz, 1H), 6.23 (s, 2H).

Example 6(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol

To a solution of example 5 (0.180 g, 0.493 mmol) in methanol (4 ml)cooled to 0° C., sodium borohydride (0.018 g, 0.493 mmol) was added andstirred for 1 h. The reaction was quenched by the addition of ice-coldwater, extracted with ethyl acetate, washed with brine, dried oversodium sulphate and concentrated. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.070 g, 39%). M.P.: 187-189° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (d, J=8.7 Hz,1H), 8.38 (d, J=8.3 Hz, 1H), 8.22 (d, J=8.3 Hz, 2H), 8.12 (d, J=8.7 Hz,1H), 8.02 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.83 (dd, J=8.7, 2.0 Hz, 1H),7.53 (dd, J=8.3, 4.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 6.20 (s, 2H), 5.32(t, J=5.7 Hz, 1H), 4.58 (d, J=5.7 Hz, 2H). MS (m/z): 367.88 (M⁺).

Example 7 Methyl4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.130 g, 0.439 mmol),4-methoxycarbonylphenylboronic acid (0.100 g, 0.562 mmol), potassiumcarbonate (0.202 g, 1.46 mmol), dioxane (2.6 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.040 g, 0.035 mmol).Off-white solid (0.100 g, 57%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(dd, J=4.2, 1.8 Hz, 1H), 8.72 (d, J=8.7 Hz, 1H), 8.39 (m, 3H), 8.21 (d,J=8.8 Hz, 1H), 8.12 (d, J=8.6 Hz, 2H), 8.02 (s, 1H), 8.02 (d, J=8.8 Hz,1H), 7.84 (dd, J=8.6, 2.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.23(s, 2H), 3.89 (s, 3H).

Example 84-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 7 (0.095 g, 0.240 mmol) in methanol (1.4 ml),lithium hydroxide (0.028 g, 1.20 mmol) in water (0.36 ml) was added andstirred at RT. After 12 h, the pH was adjusted to (approx) 7.5 using0.5N HCl and the solid precipitated was filtered, washed with ethylacetate and petroleum ether and dried under vacuum to afford the titlecompound as an off-white solid (0.070 g, 76%). M.P.: 245-247° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 13.18 (s, 1H), 8.88 (dd, J=4.1, 1.7 Hz, 1H),8.71 (d, J=8.7 Hz, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.36 (d, J=8.5 Hz, 2H),8.21 (d, J=8.7 Hz, 1H), 8.10 (d, J=8.5 Hz, 2H), 8.03 (d, J=9.2 Hz, 2H),7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s,2H). MS (m/z): 381.88 (M⁺).

Example 9N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 8 (0.050 g, 0.131 mmol) was refluxed with thionyl chloride (2ml) for 3 h. Thionyl chloride was evaporated and the residue was cooledto 0° C. and an ethanolic 50% methylamine (1 ml) was added and stirredfor 15 min. The precipitate formed was dissolved in dichloromethane,washed with sodium bicarbonate solution dried over sodium sulphate andconcentrated to afford the title compound as an off-white solid (0.020g, 39%). M.P.: 220-222° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd,J=4.2, 1.7 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.57 (q, J=4.5 Hz, 1H), 8.38(d, J=1.6 Hz, 2H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03(m, 4H), 7.84 (dd, J=8.7, 1.6 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H),6.22 (s, 2H), 2.81 (d, J=4.5 Hz, 3H). MS (m/z): 394.97 (M⁺).

Example 104-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzaldehyde

The title compound was prepared by following the procedure described forexample 1 using intermediate 15 (0.100 g, 0.380 mmol),4-formylphenylboronic acid (0.073 g, 0.487 mmol), potassium carbonate(0.175 g, 1.26 mmol), dioxane (2.3 ml), water (0.5 ml) and Tetrakis(triphenylphosphine)palladium(0) (0.035 g, 0.030 mmol). Brown solid(0.095 g, 68%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.11 (s, 1H), 8.72(d, J=8.7 Hz, 1H), 8.48 (d, J=8.3 Hz, 2H), 8.24 (d, J=8.7 Hz, 1H), 8.10(d, J=8.4 Hz, 2H), 7.55 (m, 2H), 7.22 (m, 2H), 6.01 (s, 2H).

Example 11(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol

To a solution of example 10 (0.095 g, 0.259 mmol) in methanol (2 ml)cooled to 0° C., sodium borohydride (0.010 g, 0.259 mmol) was added andstirred for 1 h. The reaction was quenched by the addition of ice-coldwater, extracted with ethyl acetate, washed with brine, dried oversodium sulphate and concentrated. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as an off-white solid (0.040 g, 46%). M.P.: 210-213° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.61 (d, J=8.7 Hz, 1H), 8.22 (d, J=8.3 Hz,2H), 8.11 (d, J=8.8 Hz, 1H), 7.53 (m, 4H), 7.21 (m, 2H), 5.98 (s, 2H),5.32 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H). MS (m/z): 335.05 (M⁺+1).

Example 12 Methyl2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.300 g, 1.01 mmol),3-fluoro-4-methoxycarbonylphenylboronic acid (0.257 g, 1.29 mmol),potassium carbonate (0.466 g, 13.37 mmol), dioxane (6 ml), water (1.2ml) and tetrakis(triphenylphosphine)palladium(0) (0.093 g, 0.081 mmol).Brown colour solid (0.300 g, 71%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.88 (dd, J=4.2, 1.8 Hz, 1H), 8.74 (d, J=8.7 Hz, 1H), 8.38 (dd, J=8.4,1.0 Hz, 1H), 8.27 (d, J=8.8 Hz, 1H), 8.24 (s, 1H), 8.22 (m, 1H),8.07-8.00 (m, 3H), 7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.63 (m, 1H), 6.24 (s,2H), 3.89 (s, 3H).

Example 132-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 12 (0.230 g, 0.556 mmol) in methanol (3.5 ml),lithium hydroxide (0.132 g, 5.56 mmol) in water (0.9 ml) was added andstirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCland the solid precipitated was filtered, washed with ethyl acetate andpetroleum ether and dried under vacuum to afford the title compound aspale brown solid (0.130 g, 61%). M.P.: 254-257° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 13.43 (s, 1H), 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.73 (d,J=8.8 Hz, 1H), 8.38 (d, J=7.5 Hz, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.19 (m,2H), 8.04 (m, 3H), 7.83 (dd, J=8.8, 2.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2Hz, 1H), 6.23 (s, 2H). MS (m/z): 400.01 (M⁺+1).

Example 142-Fluoro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 13 (0.045 g, 0.112 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Methylamine inethanol (50% solution, 3 ml) was added and stirred for 15 min. Theprecipitate formed was dissolved in dichloromethane, washed with sodiumbicarbonate solution dried over sodium sulphate and concentrated toafford title compound as pale brown solid (0.015 g, 32%). M.P.: 212-214°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.72(d, J=8.7 Hz, 1H), 8.37 (m, 2H), 8.23 (d, J=8.8 Hz, 1H), 8.18 (m, 2H),8.04 (d, J=1.7 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.83 (dd, J=8.8, 2.0 Hz,1H), 7.80 (t, J=8.1 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.23 (s, 2H),2.80 (d, J=4.6 Hz, 3H). MS (m/z): 412.96 (M⁺).

Example 152-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 13 (0.045 g, 0.112 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Aqueous ammonia(25% solution, 3 ml) was added and stirred for 15 min. The precipitateformed was dissolved in dichloromethane, washed with sodium bicarbonatesolution dried over sodium sulphate and concentrated to afford titlecompound as off-white solid (0.025 g, 56%). M.P.: 198-200° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.72 (d, J=8.7 Hz,1H), 8.38 (dd, J=8.5, 1.0 Hz, 1H), 8.23 (d, J=8.7 Hz, 1H), 8.17 (m, 2H),8.04 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.84 (m, 3H), 7.74 (brs, 1H), 7.54 (dd, J=8.3, 4.2 Hz, 1H), 6.23 (s, 2H). MS (m/z): 398.89(M⁺).

Example 16(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol

To a solution of Example 12 (0.130 g, 0.314 mmol) in THF (1.3 ml) cooledto 0° C., DIBAL-H (25% in toluene, 0.84 ml, 1.25 mmol) was added stirredat RT for 3 h. The reaction mixture was poured in ice-cold water andextracted with ethyl acetate, washed with brine, dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as pale yellow solid (0.030 g, 25%). M.P.: 202-204° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.67 (d, J=8.7Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 8.12 (dd,J=8.0, 1.5 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.65 (t,J=7.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 5.41 (t,J=5.8 Hz, 1H), 4.62 (d, J=5.6 Hz, 2H). MS (m/z): 386.01 (M⁺+1).

Example 17 Methyl4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 16 (0.300 g, 0.951 mmol),3-fluoro-4-methoxycarbonyl phenylboronic acid (0.241 g, 1.21 mmol),potassium phosphate (0.606 g, 2.856 mmol), toluene (10 ml), and Tetrakis(triphenylphosphine) palladium(0) (0.088 g, 0.076 mmol). Brown coloursolid (0.380 g, 92%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.71 (d, J=8.7Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.17 (s, 1H), 8.15 (d, J=7.2 Hz, 1H),8.06 (t, J=8.0 Hz, 1H), 7.53 (dt, J=8.9, 5.2 Hz, 1H), 7.46 (dt, J=9.1,4.2 Hz, 1H), 6.13 (s, 2H), 3.89 (s, 3H).

Example 184-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluorobenzoicacid

To a solution of Example 17 (0.300 g, 0.725 mmol) in methanol (1 ml),THF (2 ml), sodium hydroxide (0.150 g, 3.75 mmol) in water (1 ml) wasadded and stirred at RT. After 12 h, the pH was adjusted to 7-7.5 using0.5N HCl and the solid precipitated was filtered, washed with ethylacetate and petroleum ether and dried under vacuum to afford the titlecompound as a pale brown solid (0.120 g, 41%). M.P.: 211-213° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.65 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz,1H), 8.02 (m, 2H), 7.83 (t, J=7.4 Hz, 1H), 7.60 (dt, J=9.1, 4.8 Hz, 1H),7.46 (dt, J=9.0, 4.0 Hz, 1H), 6.11 (s, 2H). MS (m/z): 418.70 (M⁺).

Example 194-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-fluoro-N-methylbenzamide

To Example 18 (0.100 g, 0.250 mmol), thionyl chloride (2 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Methylamine inethanol (50% solution, 3 ml) was added and stirred for 15 min. Theprecipitate formed was filtered and washed with petroleum ether and toafford title compound as pale brown solid (0.030 g, 27%). M.P.: 213-215°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.69 (d, J=8.8 Hz, 1H), 8.36 (br s,1H), 8.22 (d, J=8.8 Hz, 1H), 8.12 (d, J=7.4 Hz, 1H), 8.10 (d, J=11.2 Hz,1H), 7.80 (t, J=7.8 Hz, 1H), 7.61 (dt, J=8.8, 4.7 Hz, 1H), 7.45 (dt,J=9.2, 4.3 Hz, 1H), 6.13 (s, 2H), 2.80 (d, J=4.3 Hz, 3H). MS (m/z):431.80 (M⁺).

Example 20N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 8 (0.090 g, 0.235 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Ethanolamine (5 ml)was added and stirred for 1 h. The precipitate formed was filtered andwashed with petroleum ether and to afford title compound as an off-whitesolid (0.022 g, 22%). M.P.: >260° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.88 (d, J=2.9 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.57 (t, J=5.4 Hz, 1H),8.38 (d, J=8.7 Hz, 1H), 8.34 (d, J=8.3 Hz, 2H), 8.21 (d, J=8.7 Hz, 1H),8.03 (m, 4H), 7.84 (d, J=8.8 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22(s, 2H), 4.76 (t, J=5.3 Hz, 1H), 3.53 (q, J=6.0 Hz, 2H), 3.36 (t,J=6.04.3 Hz, 2H).

Example 214-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 8 (0.050 g, 0.131 mmol), thionyl chloride (1 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Aqueous ammonia(25% solution, 3 ml) was added and stirred for 15 min. The precipitateformed was filtered, washed with petroleum ether and dried to affordtitle compound as a yellow solid (0.020 g, 40%). M.P.: 229-231° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.69 (d,J=8.7 Hz, 1H), 8.38 (dd, J=7.4 Hz, 1H), 8.33 (d, J=8.3 Hz, 2H), 8.21 (d,J=8.9 Hz, 1H), 8.09 (s, 1H), 8.04-8.00 (m, 4H), 7.84 (dd, J=8.8, 1.9 Hz,1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 7.48 (s, 1H), 6.22 (s, 2H). MS (m/z):380.90 (M⁺+1).

Example 22 Lithium4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

To Example 8 (0.010 g, 0.026 mmol), in methanol, lithium hydroxide (1.09m g) was and stirred at RT for 12 h. The reaction mixture wasconcentrated completely to afford title compound as a yellow solid(0.010 g, 98%). M.P.: >280° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(d, J=2.7 Hz, 1H), 8.61 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.13(m, 3H), 8.03 (s, 1H), 8.02 (d, J=8.9 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H),7.83 (d, J=7.3 Hz, 1H), 7.53 (dd, J=8.2, 4.1 Hz, 1H), 6.20 (s, 2H).

Example 236-((5-(3-(trifluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of intermediate 14 (0.120 g, 0.405 mmol) and3-trifluoromethoxyphenyl boronic acid (0.107 g, 0.519 mmol) in dioxane(2.4 ml), potassium carbonate (0.186 g, 1.35 mmol) and water (0.5 ml)were added and degassed for 30 min. Tetrakis triphenylphosphinepalladium (0) (0.037 g, 0.032 mmol) was added under nitrogen at RT andthe reaction mixture was refluxed for 12 h. The solvent was evaporatedcompletely and to the residue water was added and extracted with ethylacetate, dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as grey solid(0.090 g, 53%). M.P.: 140-142° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(dd, J=4.1, 1.6 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.35 (d, J=7.9 Hz, 1H),8.29 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.19 (s, 1H), 8.03 (s,1H), 8.01 (d, J=8.7 Hz, 1H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.71 (t,J=8.1 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 2H), 6.22 (s, 2H). MS (m/z):421.92 (M⁺).

Example 243-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenol

To a solution of example 2 (0.110 g, 0.299 mmol) in dichloromethane (1ml), BBr₃ (1M in dichloromethane, 0.82 ml) was added at 0° C. and thereaction mixture was warmed to RT and stirred for 1 h. The reactionmixture was quenched with 1.5N HCl solution and extracted withdichloromethane. The organic layer was dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as anoff-white solid (0.030 g, 28%). M.P.: 255-257° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 9.70 (s, 1H), 8.88 (dd, J=4.1, 2.6 Hz, 1H), 8.62 (d,J=8.7 Hz, 1H), 8.37 (d, J=8.0 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7,1.8 Hz, 1H), 7.64 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.53 (dd, J=8.3, 4.2Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 6.92 (dd, J=7.9, 1.4 Hz, 1H), 6.19 (s,2H). MS (m/z): 354.02 (M⁺).

Example 256-((5-(3-(difluoromethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of intermediate 14 (0.100 g, 0.405 mmol) and3-difluoromethoxyphenyl boronic acid (0.081 g, 0.438 mmol) in dioxane (3ml), potassium carbonate (0.155 g, 1.12 mmol) and water (0.5 ml) wereadded and degassed for 30 min. Tetrakis triphenylphosphine palladium (0)(0.031 g, 0.032 mmol) was added under nitrogen at RT and the reactionmixture was refluxed for 12 h. The solvent was evaporated completely andto the residue water was added and extracted with ethyl acetate, driedover sodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as an off-white solid(0.046 g, 29%). M.P.: 122-125° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.36 (d, J=8.5 Hz, 1H),8.18 (d, J=8.8 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 8.03 (m, 3H), 7.84 (dd,J=8.7, 1.5 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz,1H), 7.36 (s, 1H), 7.34 (dd, J=8.1, 2.2 Hz, 1H), 6.22 (s, 2H). MS (m/z):403.79 (M⁺).

Example 26(4-Methylpiperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone

To a solution of example 8 (0.100 g, 0.262 mmol) in DMF (1 ml) HOBT(0.042 g, 0.314 mmol), EDC-HCl (0.125 g, 0.655 mmol) and triethylamine(0.1 ml, 0.786 mmol) were added and stirred for 5 min.4-Methylpiperazine (0.023 g, 0.235 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.020 g, 17%). M.P.: 156-158° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz,1H), 8.36 (d, J=7.6 Hz, 1H), 8.31 (d, J=8.3 Hz, 2H), 8.17 (d, J=8.7 Hz,1H), 8.02 (dd, J=5.1, 3.6 Hz, 2H), 7.83 (dd, J=8.8, 1.8 Hz, 1H), 7.56(d, J=8.4 Hz, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.63 (s,2H), 3.30 (s, 2H), 2.36 (s, 4H), 2.19 (s, 3H).

Example 27N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml), HOBT(0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine(0.2 ml, 1.57 mmol) were added and stirred for 5 min.2-N,N-Dimethylethylamine (0.046 g, 0.524 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.100 g, 42%). M.P.: 122-125° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.69 (d, J=8.8 Hz,1H), 8.54 (t, J=5.4 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.33 (d, J=8.3 Hz,2H), 8.20 (d, J=8.7 Hz, 1H), 8.03-7.98 (m, 4H), 7.84 (dd, J=8.7, 1.7 Hz,1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 3.41 (q, J=6.6 Hz, 2H),2.47 (m, 2H), 2.20 (s, 6H).

Example 284-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide

To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml) HOBT(0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine(0.2 ml, 1.57 mmol) were added and stirred for 5 min.4-Aminotetrahydropyran (0.106 g, 1.04 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as an off-white solid (0.050 g, 20%). M.P.: 202-205° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.8Hz, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.38 (d, J=7.7 Hz, 1H), 8.33 (d, J=8.5Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.99 (m, 4H), 7.85 (dd, J=8.7, 1.9Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 4.04 (m, 1H), 3.89(d, J=9.7 Hz, 2H), 3.39 (t, J=10.0 Hz, 2H), 1.78 (d, J=10.5 Hz, 2H),1.63 (m, 2H).

Example 29 tert-Butyl4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)piperidine-1-carboxylate

To a solution of example 8 (0.200 g, 0.524 mmol) in DMF (1 ml), HOBT(0.084 g, 0.629 mmol), EDC-HCl (0.250 g, 1.31 mmol) and triethylamine(0.2 ml, 1.57 mmol) were added and stirred for 5 min.1-Boc-4-aminopiperidine (0.210 g, 1.04 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as an off-white solid (0.125 g, 42%). ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.40 (d,J=7.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.33 (d, J=8.5 Hz, 2H), 8.20 (d,J=8.7 Hz, 1H), 8.03-7.99 (m, 4H), 7.84 (dd, J=8.7, 1.8 Hz, 1H), 7.53(dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H), 3.99 (m, 3H), 2.87 (m, 2H), (d,J=9.9 Hz, 2H), 1.45-1.37 (m, 11H).

Example 30N-(Piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

To a solution of example 29 (0.125 g, 0.222 mmol) in THF (1 ml), ethersaturated with HCl (1.5 ml) was added at 0° C. and stirred for 15 min.The precipitate formed was washed with ether and dried under vacuum toafford the title compound as light yellow solid (0.105 g, 95%). M.P.:220-224° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.14 (d, J=3.6 Hz, 1H),8.90 (m, 3H), 8.72 (d, J=8.7 Hz, 1H), 8.67 (d, J=7.4 Hz, 1H), 8.33 (d,J=8.5 Hz, 2H), 8.28 (m, 3H), 8.11 (dd, J=8.7, 1.5 Hz, 1H), 8.05 (d,J=8.5 Hz, 2H), 7.89 (dd, J=8.3, 4.8 Hz, 1H), 6.29 (s, 2H), 4.11 (m, 1H),3.59 (m, 1H), 3.34 (m, 1H), 3.01 (m, 2H), 1.99 (m, 2H), 1.85 (m, 2H).

Example 31N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To a solution of example 13 (0.150 g, 0.375 mmol) in DMF (1.5 ml), HOBT(0.068 g, 0.454 mmol), EDC-HCl (0.180 g, 0.941 mmol) and triethylamine(0.15 ml, 1.09 mmol) were added and stirred for 5 min.2-N,N-Dimethylethylamine (0.123 g, 1.39 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.029 g, 17%). M.P.: 122-125° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (d, J=2.8 Hz, 1H), 8.72 (d, J=8.7 Hz, 1H),8.37 (d, J=8.3 Hz, 1H), 8.29 (br s, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.18(m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.84 (m, 2H), 7.53 (dd,J=8.3, 4.1 Hz, 1H), 6.23 (s, 2H), 3.39 (m, 4H), 2.49 (s, 6H).

Example 32(S)-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanonehydrochloride

To a solution of example 8 (0.100 g, 0.262 mmol) in DMF (1 ml), HOBT(0.042 g, 0.314 mmol), EDC-HCl (0.125 g, 0.655 mmol) and triethylamine(0.3 ml, 2.35 mmol) were added and stirred for 5 min.(s)-1-(pyrrolidin-2-ylmethyl)pyrrolidine (0.120 g, 0.783 mmol) was addedat RT and the reaction mixture was stirred for 12 h. To the reactionmixture water was added and extracted with ethyl acetate, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the free base as a yellow solid (0.060 g). Thefree base was dissolved in THF (5 ml), ether saturated with HCl (2 ml)was added at 0° C. and stirred for 15 min. The precipitate formed waswashed with ether and dried under vacuum to afford the title compound asa light yellow solid (0.040 g, 27%). M.P.: 120-122° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 10.00 (s, 1H), 9.09 (s, 1H), 8.77 (m, 1H), 8.72 (d,J=8.7 Hz, 1H), 8.33 (d, J=8.2 Hz, 2H), 8.22 (m, 3H), 8.04 (d, J=9.0 Hz,1H), 7.80 (m, 1H), 7.74 (d, J=8.0 Hz, 2H), 6.28 (s, 2H), 3.75-3.30 (m,9H), 2.18-1.90 (m, 8H).

Example 33(4-(2-hydroxyethyl)piperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone

To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT(0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine(0.16 ml, 1.17 mmol) were added and stirred for 5 min.(2-(piperazin-1-yl)ethanol (0.046 g, 0.353 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.025 g, 13%). M.P.: 158-160° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (d, J=2.7 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H),8.38 (d, J=7.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.17 (d, J=8.8 Hz, 1H),8.02 (t, J=4.2 Hz, 2H), 7.83 (dd, J=8.7, 1.6 Hz, 1H), 7.56 (d, J=8.4 Hz,2H), 7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.21 (s, 2H), 4.44 (t, J=5.3 Hz, 1H),3.62 (m, 2H), 3.51 (q, J=6.0 Hz, 2H), 2.42 (m, 8H).

Example 34(R)-(3-hydroxypyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanonehydrochloride

To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT(0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine(0.16 ml, 1.17 mmol) were added and stirred for 5 min.(R)-pyrrolidin-3-ol (0.030 g, 0.353 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the amideas a yellow solid (0.015 g). The amide was dissolved in THF (2 ml),ether saturated with HCl (2 ml) was added at 0° C. and stirred for 15min. The precipitate formed was washed with ether and dried under vacuumto afford the title compound as a yellow solid (0.017 g, 10%). M.P.:120-122° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.87 (d, J=2.9 Hz, 1H),8.68 (d, J=8.7 Hz, 1H), 8.38 (d, J=8.2 Hz, 1H), 8.30 (d, J=8.2 Hz, 2H),8.17 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.83 (d, J=8.7 Hz, 1H),7.69 (m, 2H), 7.52 (dd, J=8.2, 4.1 Hz, 1H), 6.21 (s, 2H), 3.61 (m, 3H),3.44 (m, 1H), 1.95-1.80 (m, 4H).

Example 35N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To a solution of example 8 (0.120 g, 0.314 mmol) in DMF (0.7 ml),N-ethyldiisopropylamine (0.041 g, 0.314 mmol) and HATU (0.119 g, 0.314mmol) were added and stirred for 5 min. (2-(piperidin-1-yl)ethanamine(0.040 g, 0.314 mmol) was added at RT and the reaction mixture wasstirred for 12 h. To the reaction mixture water was added and extractedwith ethyl acetate, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.080 g, 52%). M.P.: 104-107° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.70 (d, J=8.7 Hz,1H), 8.62 (bs, 1H), 8.38 (m, 3H), 8.21 (d, J=8.8 Hz, 1H), 8.03-7.98 (m,4H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22(s, 2H), 3.48 (bs, 2H), 2.48 (m, 6H), 1.54 (m, 6H).

Example 36N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 35 using 2-morpholinoethanamine (0.040 g, 0.314 mmol) instead of(2-(piperidin-1-yl)ethanamine Yellow solid (0.070 g, 45%). M.P.:146-149° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz,1H), 8.70 (d, J=8.7 Hz, 1H), 8.54 (t, J=4.5 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 8.34 (d, J=8.5 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.98 (m, 4H),7.84 (dd, J=8.8, 2.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s,2H), 3.57 (t, J=4.4 Hz, 4H), 3.41 (m, 2H), 2.46 (m, 6H).

Example 37N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 35 using 2-(pyrrolidin-1-yl)ethanamine (0.036 g, 0.314 mmol)instead of (2-(piperidin-1-yl)ethanamine. Yellow solid (0.065 g, 43%).M.P.: 135-137° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7Hz, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.58 (m, 1H), 8.38 (d, J=7.5 Hz, 1H),8.34 (d, J=8.4 Hz, 2H), 8.21 (d, J=8.8 Hz, 1H), 8.03 (d, J=3.5 Hz, 2H),8.00 (d, J=8.3 Hz, 2H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd, J=8.3,4.2 Hz, 1H), 6.22 (s, 2H), 3.41 (d, J=5.4 Hz, 2H), 2.49 (m, 6H), 1.68(s, 4H).

Example 38(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone

To a solution of example 8 (0.100 g, 0.262 mmol) in 1:1DMF/dichlromethane mixture (1.0 ml), BOP (0.121 g, 0.275 mmol) andtriethylamine (0.1 ml, 0.786 mmol) were added and stirred for 30 min.4-(pyrrolidin-1-yl)piperidine (0.044 g, 0.288 mmol) was added at RT andthe reaction mixture was stirred for 12 h. To the reaction mixture waterwas added and extracted with ethyl acetate, dried over sodium sulphateand concentrated under reduced pressure. The crude product was purifiedby column chromatography with methanol: dichloromethane to afford thetitle compound as a yellow solid (0.017 g, 12%). M.P.: 125-127° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.71 (d,J=8.7 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.33 (d, J=8.2 Hz, 2H), 8.19 (d,J=8.8 Hz, 1H), 8.03 (d, J=8.9 Hz, 1H), 8.00 (s, 1H), 7.83 (dd, J=8.7,1.9 Hz, 1H), 7.57 (d, J=8.2 Hz, 2H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22(s, 2H), 3.49-3.10 (m, 9H), 2.07-1.53 (m, 8H).

Example 39N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 35 using 3-N,N-dimethylaminopropylamine (0.026 g, 0.262 mmol)instead of (2-(piperidin-1-yl)ethanamine Yellow solid (0.035 g, 29%).M.P.: 132-135° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 8.88 (dd, J=4.1,1.6 Hz, 1H), 8.70 (d, J=8.8 Hz, 1H), 8.66 (t, J=5.8 Hz, 1H), 8.38 (d,J=8.3 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.8 Hz, 1H), 8.03-7.97(m, 4H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H),6.22 (s, 2H), 3.30 (m, 2H), 2.30 (t, J=7.0 Hz, 2H), 2.14 (s, 6H), 1.68(t, J=7.0 Hz, 2H).

Example 40N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

To a solution of example 8 (0.150 g, 0.393 mmol) in DMF (1 ml), HOBT(0.063 g, 0.471 mmol), EDC-HCl (0.187 g, 0.983 mmol) and triethylamine(0.16 ml, 1.17 mmol) were added and stirred for 5 min.Bis(2-methoxyethyl)amine (0.104 g, 0.786 mmol) was added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the amideas a yellow solid (0.04 g). The amide was dissolved in THF (2 ml), ethersaturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as a yellow solid (0.035 g, 17%). M.P.:126-129° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.07 (m, 1H), 8.74 (m,1H), 8.70 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 2H), 8.19 (m, 3H), 8.02(m, 1H), 7.78 (m, 1H), 7.53 (d, J=8.2 Hz, 2H), 6.27 (s, 2H), 3.64 (bs,2H), 3.58 (br.s, 2H), 3.41 (br.s, 4H), 3.30 (s, 3H), 3.16 (s, 3H).

Example 41(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanolhydrochloride

Example 16 (0.050 g. 0.129 mmol) was dissolved in THF (3 ml) andmethanol (3 ml), ether saturated with HCl (3 ml) was added at 0° C. andstirred for 15 min. The precipitate formed was washed with ether anddried under vacuum to afford the title compound as an off-white solid(0.040 g, 74%). M.P.: 190-192° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.14(d, J=3.6 Hz, 1H), 8.88 (d, J=8.1 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.24(s, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.11 (m, 2H),8.03 (dd, J=11.7, 1.5 Hz, 1H), 7.87 (dd, J=8.1, 4.8 Hz, 1H), 7.65 (t,J=7.9 Hz, 1H), 6.29 (s, 2H), 5.86 (s, 1H), 4.61 (s, 2H).

Example 426-((5-(3-Fluoro-4-(methoxymethyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

Sodium hydride (0.010 g, 0.259 mmol) was added at 0° C. to a solution ofexample 16 (0.100 g, 0.259 mmol) in DMF (1 ml) and stirred for 30 min.Methyl iodide (0.073 g, 0.518 mmol) was added and the reaction mixturewas warmed to RT. After 12 h, the reaction mixture was poured intoice-cold water and extracted with ethyl acetate, washed with brine,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with methanol: dichloromethane toafford the title compound as an off-white solid (0.033 g, 32%). M.P.:200-201° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz,1H), 8.68 (d, J=8.8 Hz, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.8 Hz,1H), 8.11-8.00 (m, 4H), 7.83 (dd, J=8.7, 1.9 Hz, 1H), 7.61 (t, J=7.7 Hz,1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.22 (s, 2H), 4.53 (s, 2H), 3.33 (s,3H).

Example 43N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To a solution of example 13 (0.100 g, 0.250 mmol) in DMF (0.7 ml),N-ethyldiisopropylamine (0.064 g, 0.50 mmol) and HATU (0.095 g, 0.250mmol) were added and stirred for 5 min. Ethylamine hydrochloride (0.020g, 0.250 mmol) was added at RT and the reaction mixture was stirred for12 h. Water was added to the reaction mixture and extracted with ethylacetate, dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford the title compound as a yellow solid(0.070 g, 66%). M.P.: 207-209° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(dd, J=4.2, 1.7 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.41 (m, 1H), 8.37 (d,J=7.6 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.17 (m, 2H), 8.04 (s, 1H), 8.02(d, J=8.8 Hz, 1H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H),7.54 (dd, J=8.3, 4.1 Hz, 1H), 6.23 (s, 2H), 3.29 (m, 2H), 1.4 (t, J=7.2Hz, 3H).

Example 442-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using (2-(piperidin-1-yl)ethanamine (0.028 g, 0.250 mmol)instead of ethylamine hydrochloride. Yellow solid (0.015 g, 12%). M.P.:183-186° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.89 (dd, J=4.0, 1.5 Hz,1H), 8.74 (d, J=8.7 Hz, 1H), 8.59 (m, 1H), 8.37 (d, J=7.7 Hz, 1H),8.25-8.19 (m, 3H), 8.03 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.90 (t, J=8.0Hz, 1H), 7.84 (dd, J=8.7, 1.8 Hz, 1H), 7.54 (dd, J=8.4, 4.2 Hz, 1H),6.24 (s, 2H), 3.62 (m, 4H), 3.06-2.89 (m, 4H), 1.89-1.86 (m, 4H).

Example 45N-cyclohexyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using cyclohexylamine (0.025 g, 0.250 mmol) instead ofethylamine hydrochloride. Yellow solid (0.050 g, 41%). M.P.: 172-175° C.MS (m/z): 481.21 (M⁺+1).

Example 46N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using cyclopropylamine (0.014 g, 0.250 mmol) instead ofethylamine hydrochloride. Off-white solid (0.015 g, 14%). M.P.: 193-195°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.71(d, J=8.7 Hz, 1H), 8.48 (d, J=3.8 Hz, 1H), 8.37 (d, J=7.3 Hz, 1H), 8.23(d, J=8.8 Hz, 1H), 8.16 (m, 2H), 8.04 (s, 1H), 8.02 (d, J=8.7 Hz, 1H),7.83 (dd, J=8.7, 2.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.54 (dd, J=8.4,4.2 Hz, 1H), 6.23 (s, 2H), 2.87 (m, 1H), 0.70 (m, 2H), 0.57 (m, 2H).

Example 472-Fluoro-N-(pyridin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using 4-aminopyridine (0.023 g, 0.250 mmol) instead ofethylamine hydrochloride. Yellow solid (0.050 g, 42%). M.P.: 217-219° C.MS (m/z): 476.17 (M⁺+1).

Example 48N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using benzylamine (0.023 g, 0.250 mmol) instead of ethylaminehydrochloride. Pale green solid (0.040 g, 32%). M.P.: 163-165° C. MS(m/z): 489.19 (M⁺+1).

Example 492-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using dimethylamine hydrochloride (0.020 g, 0.250 mmol)instead of ethylamine hydrochloride. Pale brown solid (0.020 g, 18%).M.P.: 163-165° C. MS (m/z): 426.96 (M⁺+1).

Example 50 Methyl2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)acetate

To glycine (0.100 g, 1.133 mmol) in methanol (4 ml), thionyl chloride(0.9 ml) was added and refluxed for 1 h. The solvent was removed and theresidue was dissolved in DMF (2 ml). To this solution example 13 (0.150g, 0.375 mmol), N-ethyldiisopropylamine (0.097 g, 0.751 mmol) and HATU(0.0142 g, 0.375 mmol) were added at RT and the reaction mixture wasstirred for 12 h. To the reaction mixture water was added and extractedwith ethyl acetate, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.055 g, 31%). ¹H-NMR (δ ppm, CDCl₃, 400MHz): δ 8.92 (dd, J=4.2, 1.6 Hz, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.27 (t,J=8.4 Hz, 1H), 8.16 (d, J=8.8 Hz, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.00 (m,3H), 7.88 (m, 2H), 7.43 (dd, J=8.4, 4.2 Hz, 1H), 7.36 (m, 1H), 6.16 (s,2H), 4.32 (d, J=4.7 Hz, 2H), 3.83 (s, 3H).

Example 512-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)aceticacid

To a solution of Example 50 (0.055 g, 0.113 mmol) in methanol (0.5 ml),lithium hydroxide (0.045 g, 1.05 mmol) in water (0.5 ml) was added andstirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl andthe solid precipitated was filtered, washed with ethyl acetate andpetroleum ether and dried under vacuum to afford the title compound as apale green solid (0.050 g, 96%). M.P.: 252-254° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 12.70 (s, 1H), 9.01 (d, J=3.9 Hz, 1H), 8.73 (d, J=8.7Hz, 1H), 8.64 (m, 2H), 8.25 (d, J=8.8 Hz, 1H), 8.20 (m, 4H), 7.97 (d,J=8.9 Hz, 1H), 7.86 (t, J=8.1 Hz, 1H), 7.71 (dd, J=7.8, 4.2 Hz, 1H),6.27 (s, 2H), 3.96 (d, J=5.8 Hz, 2H). MS (m/z): 456.85 (M⁺).

Example 522-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using 3-amino-1,2,4-triazole (0.021 g, 0.250 mmol) instead ofethylamine hydrochloride. Off-white solid (0.010 g, 9%). M.P.: 265-267°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.70 (s, 1H), 12.10 (s, 1H), 8.87(m, 1H), 8.74 (d, J=8.5 Hz, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.27-8.22 (m,3H), 8.05 (m, 2H), 7.89-7.79 (m, 3H), 7.54 (q, J=4.2 Hz, 1H), 6.25 (s,2H). MS (m/z): 465.95 (M⁺).

Example 53 Methyl3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.250 g, 0.845 mmol),3-methoxycarbonylphenylboronic acid (0.190 g, 1.056 mmol), potassiumacetate (0.276 g, 2.81 mmol), dioxane (5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.078 g, 0.067 mmol). Brownsolid (0.190 g, 56%).

Example 543-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of example 53 (0.190 g, 0.480 mmol) in methanol (2.7 ml),lithium hydroxide (0.201 g, 4.80 mmol) in water (0.75 ml) was added andstirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCland the solid precipitated was filtered, washed with ethyl acetate andpetroleum ether and dried under vacuum to afford the title compound asbrown solid (0.070 g, 38%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.39 (s,1H), 8.87 (d, J=2.6 Hz, 1H), 8.77 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.39(m, 2H), 8.16 (d, J=8.7 Hz, 1H), 8.07 (m, 3H), 7.85 (dd, J=8.7, 1.5 Hz,1H), 7.66 (t, J=7.8 Hz, 1H), 7.52 (dd, J=8.3, 4.1 Hz, 1H), 6.22 (s, 2H).

Example 55N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To example 54 (0.070 g, 0.183 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Methylamine inethanol (50% solution, 5 ml) was added and stirred for 15 min. Theprecipitate formed was washed with sodium bicarbonate solution and driedunder vacuum to afford the title compound as pale brown solid (0.050 g,69%). M.P.: 215-217° C. MS (m/z): 359.04 (M⁺+1).

Example 566-((5-(3-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),3-fluorophenylboronic acid (0.059 g, 0.422 mmol), potassium carbonate(0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Yellow solid (0.040 g, 30%.M.P.: 145-147° C. MS (m/z): 356.05 (M⁺+1).

Example 57 Methyl3-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenylamino)propanoate

To 2-aminopropionic acid (0.100 g, 1.122 mmol) in methanol (4 ml),thionyl chloride (0.9 ml) was added and refluxed for 1 h. Solvents wereremoved and residue was dissolved in DMF (2 ml). To this solutionexample 13 (0.150 g, 0.375 mmol), N-ethyldiisopropylamine (0.097 g,0.751 mmol) and HATU (0.0142 g, 0.375 mmol) were added at RT and thereaction mixture was stirred for 12 h. To the reaction mixture water wasadded and extracted with ethyl acetate, dried over sodium sulphate andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.078 g, 44%).

Example 583-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenylamino)propanoicacid

To a solution of example 57 (0.080 g, 0.165 mmol) in methanol (0.8 ml),lithium hydroxide (0.064 g, 1.54 mmol) in water (0.8 ml) was added andstirred at RT. After 12 h, pH was adjusted to ca. 7.5 using 0.5N HCl andthe solid precipitated was filtered, washed with ethyl acetate andpetroleum ether and dried under vacuum to afford the title compound aspale green solid (0.075 g, 68%). M.P.: 132-135° C.

Example 592-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

The title compound was prepared by following the procedure described forexample 43 using N,O-dimethylhydroxylamine hydrochloride (0.025 g, 0.250mmol) instead of Ethylamine hydrochloride. Yellow solid (0.055 g, 46%).M.P.: 201-202° C. MS (m/z): 443.20 (M⁺+1-HCl).

Example 60N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using tert-butylamine (0.018 g, 0.250 mmol) instead ofethylamine hydrochloride. Yellow solid (0.050 g, 44%). M.P.: 210-212° C.MS (m/z): 455.10 (M⁺+1).

Example 61N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using allylamine (0.018 g, 0.250 mmol) instead of ethylaminehydrochloride. Yellow solid (0.033 g, 29%). M.P.: 162-164° C. MS (m/z):438.93 (M⁺).

Example 622-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using methoxylamine hydrochloride (0.0208 g, 0.250 mmol)instead of ethylamine hydrochloride. Yellow solid (0.055 g, 51%). M.P.:197-199° C. MS (m/z): 429.06 (M⁺).

Example 63N-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)acetamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),4-acetamidophenylboronic acid (0.076 g, 0.422 mmol), potassium carbonate(0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Brown solid (0.090 g, 67%).M.P.: 220-223° C. MS (m/z): 394.83 (M⁺1).

Example 644-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline

To a solution of example 63 (0.060 g, 0.152 mmol) in ethanol (1 ml) wasadded con. HCl (0.5 ml) and refluxed for 2 h. The reaction mixture wascooled, basified with sodium bicarbonate solution, extracted with ethylacetate, dried over sodium sulphate and concentrated under reducedpressure to afford the title compound as a brown solid (0.030 g, 42%).M.P.: 190-193° C. MS (m/z): 353.18 (M⁺+1).

Example 656-((5-(3,4-Dimethoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),3,4-dimethoxyphenylboronic acid (0.076 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Brown solid (0.090 g, 67%).M.P.: 149-152° C. MS (m/z): 397.77 (M⁺).

Example 666-((5-(3-Fluoro-4-methoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),3-fluoro-4-methoxyphenylboronic acid (0.074 g, 0.439 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Pale green solid (0.060 g,46%). M.P.: 187-190° C. MS (m/z): 385.873 (M⁺).

Example 676-((5-(4-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),4-fluorophenylboronic acid (0.059 g, 0.422 mmol), potassium carbonate(0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Yellow solid (0.060 g, 50%).M.P.: 153-156° C. MS (m/z): 355.98 (M⁺).

Example 686-((5-(2-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-fluorophenylboronic acid (0.059 g, 0.422 mmol), potassium carbonate(0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Yellow solid (0.050 g, 41%).M.P.: 164-166° C. MS (m/z): 355.84 (M⁺).

Example 69N-(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)acetamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),4-acetamidophenylboronic acid (0.078 g, 0.439 mmol), potassium carbonate(0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Pale green solid (0.065 g,49%). M.P.: 198-201° C. MS (m/z): 395.11 (M⁺+1).

Example 706-((5-(3-(2,2,2-Trifluoroethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),3-trifluoroethoxyphenylboronic acid (0.096 g, 0.439 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 20 min. Off-white solid (0.040 g,42.7%). M.P.: 151-154° C. MS (m/z): 435.97 (M⁺).

Example 713-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline

To a solution of example 69 (0.045 g, 0.152 mmol) in ethanol (1 ml),con. HCl (0.5 ml) was added and refluxed for 2 h. The reaction mixturewas cooled, basified with sodium bicarbonate solution, extracted withethyl acetate, dried over sodium sulphate and concentrated under reducedpressure to afford the title compound as brown solid (0.028 g, 70%).M.P.: 187-189° C. MS (m/z): 352.90 (M⁺).

Example 72N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using 3-N,N-Dimethylaminopropylamine (0.026 g, 0.262 mmol)instead of ethylamine hydrochloride. Off-white solid (0.063 g, 54%).M.P.: 148-150° C. MS (m/z): 483.92 (M⁺).

Example 73N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

The example 43 (0.050 g, 0.117 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.052 g, 95%). M.P.:236-238° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.07 (m, 1H), 8.73 (m,2H), 8.41 (m, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.19-8.13 (m, 4H), 8.02 (d,J=7.4 Hz, 1H), 7.80 (m, 2H), 6.29 (s, 2H), 3.23 (m, 2H), 1.14 (t, J=7.2Hz, 3H).

Example 742-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

The example 15 (0.040 g. 0.100 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.043 g, 96%). M.P.:165-1688° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 9.10 (m, 1H), 8.79 (m,1H), 8.73 (d, J=8.8 Hz, 1H), 8.24-8.13 (m, 4H), 8.05 (d, J=8.7 Hz, 1H),7.83 (m, 3H), 7.74 (s, 1H), 6.29 (s, 2H).

Example 756-((5-(3-Fluoro-4-isopropoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),3-fluoro-4-isopropoxyphenylboronic acid pinacol ester (0.113 g, 0.439mmol), potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water(0.5 ml) and tetrakis (triphenylphosphine)palladium(0) (0.031 g, 0.067mmol) in microwave oven (100 W, 100° C.) for 30 min. Brown solid (0.095g, 68%). M.P.: 128-130° C. MS (m/z): 413.92 (M⁺).

Example 76N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using intermediate 23 (0.075 g, 0.326 mmol) instead ofEthylamine hydrochloride. Off-white solid (0.075 g, 60%). M.P.: 163-165°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.91 (dd, J=4.2, 1.6 Hz, 1H), 8.46(d, J=8.7 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.17 (d, J=9.3 Hz, 1H), 8.10(d, J=8.7 Hz, 1H), 7.97-7.83 (m, 5H), 7.78 (m, 1H), 7.43 (dd, J=8.3, 4.2Hz, 1H), 6.15 (s, 2H), 3.84 (q, J=5.4 Hz, 1H), 2.68 (t, J=5.5 Hz, 2H),3.01 (s, 3H), 2.98 (s, 3H). MS (m/z): 498.41 (M⁺+1).

Example 77N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using intermediate 24 (0.050 g, 0.280 mmol) instead ofEthylamine hydrochloride. Off-white solid (0.085 g, 70%). M.P.: 177-179°C. MS (m/z): 483.85 (M⁺).

Example 782-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using intermediate 25 (0.096 g, 0.396 mmol) instead ofEthylamine hydrochloride. Off-white solid (0.085 g, 66%). M.P.: 175-177°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.91 (dd, J=4.1, 1.5 Hz, 1H), 8.47(d, J=8.6 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 1H), 8.10(d, J=8.7 Hz, 1H), 7.98 (m, 4H), 7.87 (dd, J=8.7, 3.2 Hz, 2H), 7.43 (dd,J=8.3, 4.2 Hz, 1H), 6.15 (s, 2H), 4.25 (d, J=3.5 Hz, 2H), 3.58 (t, J=5.9Hz, 2H), 3.48 (t, J=5.8 Hz, 2H), 2.06 (q, J=6.9 Hz, 2H), 1.94 (q, J=6.8Hz, 2H). MS (m/z): 509.96 (M⁺).

Example 796-((5-(4-(Cyclopropylmethoxy)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.123 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027 mmol),dioxane (2 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave oven(100 W, 100° C.) for 30 min. Off-white solid (0.040 g, 28%). M.P.:160-162° C. MS (m/z): 425.89 (M⁺).

Example 806-((5-(3-Fluoro-4-isobutoxyphenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),4-isobutyloxy-3-fluorophenyl boronic acid pinacol ester (0.122 g, 0.422mmol), potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water(0.5 ml) and tetrakis (triphenylphosphine)palladium(0) (0.031 g, 0.067mmol) in microwave oven (100 W, 100° C.) for 30 min. Pale brown solid(0.065 g, 45%). M.P.: 115-157° C. MS (m/z): 428.13 (M⁺+1).

Example 813-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenoxy)-N,N-dimethylpropan-1-amine

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-N,N-dimethylpropan-1-amine(0.137 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027 mmol),dioxane (2 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave oven(100 W, 100° C.) for 30 min. Pale brown solid (0.055 g, 45%). M.P.:102-105° C. MS (m/z): 457.18 (M⁺+1).

Example 82 Methyl2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 17 (0.600 g, 1.841 mmol),3-fluoro-4-methoxycarbonyl phenylboronic acid (0.459 g, 2.30 mmol),potassium acetate (0.585 g, 5.965 mmol), dioxane (12 ml) andtetrakis(triphenylphosphine)palladium(0) (0.170 g, 0.147 mmol).Off-white solid (0.705 g, 87%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.90(dd, J=4.2, 1.5 Hz, 1H), 8.44 (d, J=8.7 Hz, 1H), 8.18 (d, J=7.8 Hz, 1H),8.00 (d, J=9.0 Hz, 1H), 7.92 (m, 2H), 7.75 (d, J=8.7 Hz, 1H), 7.69-7.60(m, 3H), 7.41 (m, 1H), 3.93 (s, 3H), 2.50 (s, 6H).

Example 832-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 82 (0.700 g, 1.60 mmol) in methanol (3.7 ml),lithium hydroxide (0.626 g, 14.94 mmol) in water (3.7 ml) and THF (14ml) were added and stirred at RT. After 12 h, the pH was adjusted to7-7.5 using 0.5N HCl and the solid precipitated was filtered, washedwith ethyl acetate and petroleum ether and dried under vacuum to affordthe title compound as an off-white solid (0.485 g, 71%) MS (m/z): 472.99(M⁺).

Example 842-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 83 (0.050 g, 0.116 mmol), thionyl chloride (1 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Aqueous ammonia(25% solution, 3 ml) was added and stirred for 15 min. The precipitateformed was washed with sodium bicarbonate solution and vacuum dried toafford title compound as brown solid (0.025 g, 50%). M.P.: 127-130° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.87 (d, J=2.5 Hz, 1H), 8.67 (d, J=8.9Hz, 1H), 8.42 (d, J=7.9 Hz, 1H), 8.11 (d, J=8.9 Hz, 1H), 8.09 (s, 1H),7.91 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.71-7.61 (m, 4H), 7.75(m, 2H), 2.48 (s, 6H).

Example 856-((5-(3-Fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-(3-fluoro-4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.109 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027 mmol),dioxane (2 ml), water (0.5 ml) and Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) in microwave oven(100 W, 100° C.) for 30 min. Pale brown solid (0.055 g, 35%). M.P.:165-167° C. MS (m/z): 455.85 (M⁺).

Example 866-((5-(3-Fluoro-4-(2-methoxyethoxy)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.125 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027 mmol),dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 30 min. Pale yellow solid (0.060 g,41%). M.P.: 122-124 C. MS (m/z): 430.02 (M⁺+1).

Example 872-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using propylamine (0.015 g, 0.250 mmol) instead of ethylaminehydrochloride. Pale yellow solid (0.070 g, 63%). M.P.: 157-159° C. MS(m/z): 440.87 (M⁺).

Example 886-((5-(4-(Cyclopropylcarbamoyl)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline1-oxide

To a solution of example 46 (0.080 g, 0.182 mmol) in dichloromethane (1ml), m-chloroperbenzoic acid (0.044 g, 0.255 mmol) was added and stirredat RT for 12 h. The reaction mixture was quenched with sodium sulphitesolution, washed with saturated potassium carbonate solution andconcentrated. The crude product was chromatographed using methanol:dichloromethane to afford the title compound as a pale yellow solid(0.025 g, 30%). M.P.: 89-92° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(dd, J=4.1, 1.6 Hz, 1H), 8.75 (d, J=9.0 Hz, 1H), 8.51 (m, 2H), 8.28 (t,J=8.1 Hz, 1H), 7.98-7.86 (m, 5H), 7.71 (d, J=8.5 Hz, 1H), 7.32 (dd,J=8.5, 6.1 Hz, 1H), 6.89 (d, J=11.8 Hz, 1H), 6.15 (s, 2H), 2.99 (m, 1H),0.94 (m, 2H), 0.69 (m, 2H).

Example 89N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

The example 46 (0.045 g. 0.102 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.046 g, 95%). M.P.:105-107° C. MS (m/z): 439.12 (M⁺+1-HCl).

Example 90N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using cyclopropylmethylamine (0.018 g, 0.250 mmol) instead ofethylamine hydrochloride. Off-white solid (0.085 g, 75%). M.P.: 120-122°C. MS (m/z): 452.91 (M⁺).

Example 91N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using n-butylamine (0.019 g, 0.250 mmol) instead ofethylamine hydrochloride. Off-white solid (0.064 g, 56%). M.P.: 100-102°C. MS (m/z): 455.08 (M⁺).

Example 922-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using furfurylamine (0.024 g, 0.250 mmol) instead ofethylamine hydrochloride. Brown solid (0.060 g, 50%). M.P.: 144-147° C.MS (m/z): 479.02 (M⁺).

Example 932-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide

The title compound was prepared by following the procedure described forexample 43 using 2,2,2,-trifluoroethylamine (0.024 g, 0.250 mmol)instead of ethylamine hydrochloride. Pale yellow solid (0.060 g, 50%).M.P.: 194-196° C. MS (m/z): 481.12 (M⁺).

Example 942-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using 2-methoxyethylamine (0.019 g, 0.250 mmol) instead ofethylamine hydrochloride. Pale green solid (0.060 g, 52%). M.P.:162-164° C. MS (m/z): 456.83 (M⁺).

Example 95N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzenesulfonamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.102 g, 0.338 mmol),4-(N-isopropylsulfamoyl)phenylboronic acid (0.102 g, 0.422 mmol),potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol)in microwave oven (100 W, t100° C.) for 30 min. Green solid (0.050 g,30%). M.P.: 154-156° C. MS (m/z): 458.79 (M⁺).

Example 96N,N-Dimethyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)aniline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.102 g, 0.338 mmol), 3-(dimethylamino)phenylboronic acid (0.072 g, 0.422 mmol), potassium carbonate (0.156 g,0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 30 min. Green solid (0.040 g, 31%).M.P.: 124-126° C. MS (m/z): 380.88 (M⁺).

Example 972-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using isobutylamine (0.018 g, 0.250 mmol) instead ofethylamine hydrochloride. Off-white solid (0.050 g, 44%). M.P.: 158-160°C. MS (m/z): 455.01 (M⁺+1).

Example 98N-Cyclopentyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using cyclopentylamine (0.021 g, 0.250 mmol) instead ofethylamine hydrochloride. Pale green solid (0.040 g, 34%). M.P.:166-168° C. MS (m/z): 467.12 (M⁺+1).

Example 992-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using isopropylamine (0.029 g, 0.500 mmol) instead ofethylamine hydrochloride. Off-white solid (0.060 g, 54%). M.P.: 177-179°C. MS (m/z): 440.87 (M⁺).

Example 100 Methyl2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (1.00 g, 3.07 mmol),3-chloro-4-methoxycarbonylphenylboronic acid (0.825 g, 3.84 mmol),potassium acetate (0.976 g, 9.945 mmol), dioxane (20 ml) andtetrakis(triphenylphosphine)palladium(0) (0.284 g, 0.246 mmol). Reddishbrown solid (1.00 g, 71%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.92 (dd,J=4.2, 1.6 Hz, 1H), 8.48 (d, J=8.6 Hz, 1H), 8.24 (d, J=1.3 Hz, 1H), 8.17(d, J=8.3 Hz, 1H), 8.10 (d, J=11.8 Hz, 1H), 8.04 (m, 3H), 7.87 (m, 2H),7.43 (q, J=4.2 Hz, 1H), 6.15 (s, 2H), 3.98 (s, 3H).

Example 1012-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 100 (1.00 g, 2.18 mmol) in methanol (5 ml),lithium hydroxide (0.856 g, 20.40 mmol) in water (5 ml) and THF (19 ml)were added and stirred at RT. After 12 h, pH was adjusted to 7-7.5 using0.5N HCl and the solid precipitated was filtered, washed with ethylacetate and petroleum ether and dried under vacuum to afford the titlecompound as an off-white solid (0.900 g, 93%).

Example 1022-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing the example 13 with example 101 (0.100 g, 0.240mmol) and using propylamine (0.028 g, 0.480 mmol) instead of ethylaminehydrochloride. Brown solid (0.043 g, 39%). M.P.: 128-130° C. MS (m/z):456.83 (M⁺+1).

Example 1032-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 83 (0.100 g, 0.234 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Methylamine inethanol (50% solution, 5 ml) was added and stirred for 15 min. Theprecipitate formed was filtered, washed with sodium bicarbonatesolution, dried over sodium sulphate and concentrated to afford titlecompound as a yellow solid (0.028 g, 27%). M.P.: 171-173° C. MS (m/z):440.94 (M⁺).

Example 104N-Cyclobutyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by using cyclobutylamine (0.035 g, 0.500 mmol) instead ofethylamine hydrochloride. Off-white solid (0.050 g, 44%). M.P.: 171-174°C. MS (m/z): 452.91 (M⁺).

Example 1052-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing the example 13 with example 83 (0.100 g, 0.234mmol) and using propylamine (0.027 g, 0.468 mmol) instead of ethylaminehydrochloride. Pale green solid (0.050 g, 47%). M.P.: 162-164° C. MS(m/z): 468.94 (M⁺).

Example 106N-Cyclopropyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing the example 13 with example 83 (0.080 g, 0.187mmol) and using cyclopropylamine (0.021 g, 0.374 mmol) instead ofethylamine hydrochloride. Pale green solid (0.015 g, 17%). M.P.:156-159° C. MS (m/z): 466.98 (M⁺).

Example 107N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing the example 13 with example 83 (0.080 g, 0.187mmol) and ethylamine hydrochloride (0.015 g, 0.187 mmol). Pale greensolid (0.015 g, 17%). M.P.: 132-135° C. MS (m/z): 454.94 (M⁺).

Example 1082-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 101 (0.100 g, 0.240 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Aqueous 25% ammonia(4 ml) was added and stirred for 15 min. The precipitate formed waswashed with sodium bicarbonate solution and vacuum dried to afford titlecompound as a brown solid (0.060 g, 60%). M.P.: 212-215° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 2.6 Hz, 1H), 8.70 (d, J=8.7 Hz,1H), 8.37 (d, J=8.3 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=8.1 Hz, 1H), 8.21(d, J=8.8 Hz, 1H), 8.04 (m, 3H), 7.83 (dd, J=8.7, 1.6 Hz, 1H), 7.69 (s,1H), 7.61 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.23 (s, 2H).MS (m/z): 415.11 (M⁺).

Example 1092-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 101 (0.100 g, 0.240 mmol), thionyl chloride (3 ml) was addedand refluxed for 3 h. The excess thionyl chloride was removed underreduced pressure and the residue was cooled to 0° C. Methylamine inethanol (50% solution, 4 ml) was added and stirred for 15 min. Theprecipitate formed was filtered, washed with sodium bicarbonate solutionand diethyl ether and vacuum dried to afford title compound as palebrown solid (0.060 g, 58%). M.P.: 227-230° C. MS (m/z): 429.04 (M⁺+1).

Example 1102-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

The example 62 (0.040 g. 0.093 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.030 g, 69%). M.P.:145-147° C. MS (m/z): 429.46 (M⁺+1-HCl).

Example 1112-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(thiazol-2-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by using 2-aminothiazole (0.050 g, 0.500 mmol) instead ofethylamine hydrochloride. Pale brown solid (0.016 g, 13%). M.P.:204-206° C. MS (m/z): 481.89 (M⁺).

Example 112N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To a solution of example 13 (0.150 g, 0.375 mmol) in DMF (1 ml)N-ethyldiisopropylamine (0.048 g, 0.375 mmol) and HATU (0.143 g, 0.375mmol) were added and stirred for 5 min. N-boc-1,3-diaminopropane (0.130g, 0.751 mmol) was added at RT and the reaction mixture was stirred for12 h. To the reaction mixture water was added and extracted with ethylacetate, dried over sodium sulphate and concentrated under reducedpressure. The crude product was purified by column chromatography withmethanol: dichloromethane to afford N-boc-protected amide (0.200 g). Theamide was dissolved in dichloromethane (1 ml) and trifluoroacetic acid(0.5 ml) was added and stirred at RT for 1 h. The reaction mixture wasquenched with sodium bicarbonate solution, extracted withdichloromethane, dried over sodium sulphate and concentrated to affordthe title compound as a pale brown solid (0.160 g, 93%). M.P.: 292-294°C. MS (m/z): 456.270 (M⁺+1).

Example 1132-Chloro-N-cyclopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing the example 13 with example 101 (0.100 g, 0.240mmol) and using cyclopropylamine (0.028 g, 0.480 mmol) instead ofethylamine hydrochloride. Off-white solid (0.047 g, 43%). M.P.: 197-199°C. MS (m/z): 455.08 (M⁺+1).

Example 1142-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using intermediate 26 (0.080 g, 0.312 mmol) instead ofethylamine hydrochloride. Off-white solid (0.075 g, 57%). M.P.: 151-153°C. MS (m/z): 524.24 (M⁺+1).

Example 1152-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by using hydroxylamine hydrochloride (0.035 g, 0.500 mmol)instead of ethylamine hydrochloride. Off-white solid (0.010 g, 9%).M.P.: 180-182° C. MS (m/z): 415.31 (M⁺+1).

Example 116N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by using example 8 (0.100 g, 0.262 mmol) and isopropylamine(0.031 g, 0.524 mmol) instead of ethylamine hydrochloride. Off-whitesolid (0.080 g, 72%). M.P.: 181-183° C. MS (m/z): 423.37 (M⁺+1).

Example 1172-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using intermediate 27 (0.135 g, 0.500 mmol) instead ofethylamine hydrochloride. Off-white solid (0.025 g, 19%). M.P.: 109-111°C. MS (m/z): 538.03 (M⁺).

Example 1181-Ethyl-3-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)urea

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.102 g, 0.338 mmol),4-(3-ethylureido)phenylboronic acid (0.123 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) inmicrowave oven (100 W, 100° C.) for 30 min. Brown solid (0.060 g, 42%).M.P.: 193-196° C. MS (m/z): 424.28 (M⁺+1).

Example 1192-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing the example 13 with example 101 (0.100 g, 0.240mmol) and ethylamine hydrochloride. Off-white solid (0.050 g, 47%).M.P.: 187-190° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.4Hz, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.51 (d, J=5.4 Hz, 1H), 8.37 (d, J=8.3Hz, 1H), 8.31 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.21 (d, J=8.0 Hz, 1H),8.04 (s, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.58 (d,J=8.0 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.23 (s, 2H), 3.30 (m, 2H),1.14 (t, J=7.2 Hz, 3H). MS (m/z): 443.04 (M⁺).

Example 1202-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using intermediate 28 (0.136 g, 0.500 mmol) instead ofethylamine hydrochloride. Pale yellow solid (0.025 g, 19%). M.P.:212-215° C. MS (m/z): 540.13 (M⁺+1).

Example 121N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidedihydrochloride

Ether saturated with HCl (1 ml) was added at 0° C. to a solution ofexample 72 (0.040 g. 0.082 mmol) in THF (1 ml), and stirred for 15 min.The precipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.040 g, 88%). M.P.:137-140° C. MS (m/z): 483.54 (M⁺-2HCl).

Example 1222-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 by replacing example 13 with example 101 (0.100 g, 0.240mmol) and 3-amino-1,2,4-triazole (0.040 g, 0.480 mmol) instead ofethylamine hydrochloride. Pale green solid (0.015 g, 13%). M.P.:286-288° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (d, J=3.7 Hz, 1H),8.74 (d, J=8.7 Hz, 1H), 8.40-8.32 (m, 3H), 8.26 (d, J=8.7 Hz, 1H), 8.05(s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.87-7.82 (m, 4H), 7.54 (s, 1H), 7.53(dd, J=8.4, 4.2 Hz, 1H), 6.24 (s, 2H). MS (m/z): 482.03 (M⁺).

Example 1232-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

Example 108 (0.150 g. 0.360 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.060 g, 46%). M.P.:273-275° C.

Example 1242-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 using 3-(piperidin-1-yl)propan-1-amine (0.086 g, 0.500 mmol)instead of ethylamine hydrochloride. Off-white solid (0.040 g, 30%).M.P.: 135-137° C. MS (m/z): 524.52 (M⁺+1).

Example 125N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidedihydrochloride

Example 112 (0.130 g. 0.287 mmol) was dissolved in THF (2 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.090 g, 64%). M.P.:290-293° C.

Example 1262-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidedihydrochloride

The title compound was prepared by following the procedure described forexample 43 by replacing example 13 with example 101 (0.150 g, 0.360mmol) and 3-N,N-dimethylaminopropylamine (0.072 g, 0.720 mmol) insteadof ethylamine hydrochloride and hydrochloride salt formation with ethersaturated with HCl (2 ml). Pale yellow solid (0.045 g, 22%). M.P.:185-187° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.11 (br. s, 1H), 9.06(d, J=4.4 Hz, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.71 (m, 2H), 8.33 (s, 1H),8.27 (m, 2H), 8.17 (m, 2H), 8.00 (d, J=8.7 Hz, 1H), 7.79 (dd, J=8.1, 4.1Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 6.28 (s, 2H). 3.34 (q, J=6.5 Hz, 2H),3.13 (m, 2H), 2.76 (s, 3H), 2.75 (s, 3H), 1.93 (m, 2H).

Example 1272-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamidehydrochloride

The example 52 (0.026 g. 0.055 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (0.5 ml) was added at 0° C. and stirred for 15 min.The precipitate formed was washed with ether and dried under vacuum toafford the title compound as an off-white solid (0.024 g, 87%). M.P.:274-276° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): δ 11.74 (br s, 1H), 9.06(d, J=4.1 Hz, 1H), 8.79 (m, 2H), 8.79 (m, 2H), 8.35-8.12 (m, 6H), 8.02(m, 2H), 7.87 (m, 1H), 7.78 (dd, J=8.0, 4.7 Hz, 1H), 6.30 (s, 2H).

Example 128 Methyl2,6-difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (1.15 g, 3.91 mmol),3,5-difluoro-4-methoxycarbonyl phenylboronic acid (prepared according toKrzysztof Durka et. al in Eur. J. Org. Chem. 2009, 4325-4332, 1.10 g,5.09 mmol), potassium acetate (1.276 g, 13.03 mmol), dioxane (20) andtetrakis(triphenylphosphine)palladium(0) (0.361 g, 0.31346 mmol). Brownsolid (0.620 g, 37%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.91 (d, J=2.9Hz, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.10 (d, J=8.7Hz, 1H), 7.97 (s, 1H), 7.86 (dd, J=8.8, 1.4 Hz, 1H), 7.81 (d, J=8.6 Hz,1H), 7.74 (d, J=9.1 Hz, 2H), 7.43 (dd, J=8.4, 4.2 Hz, 1H), 6.15 (s, 2H),3.99 (s, 3H).

Example 1292,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 128 (0.70 g, 1.62 mmol) in methanol (3.8 ml),lithium hydroxide (0.635 g, 15.13 mmol) in water (3.8 ml) and THF (14.3ml) were added and stirred at RT. After 12 h, pH was adjusted to ca. 7using 0.5N HCl and the solid precipitated was filtered, washed withethyl acetate and petroleum ether and dried under vacuum to afford thetitle compound as pale brown solid (0.50 g, 74%).

Example 1302,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 102 using Example 129 (0.500 g, 1.19 mmol), thionyl chloride (10ml) and aqueous 25% ammonia (7 ml). Off-white solid (0.400 g, 81%).M.P.: 272-275° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (d, J=3.9 Hz,1H), 8.74 (d, J=8.8 Hz, 1H), 8.37 (d, J=7.8 Hz, 1H), 8.25 (d, J=8.9 Hz,1H), 8.20 (s, 1H), 8.07 (m, 3H), 8.01 (d, J=8.5 Hz, 1H), 7.93 (s, 1H),7.83 (d, J=6.8 Hz, 1H), 7.53 (dd, J=8.6, 4.4 Hz, 1H), 6.24 (s, 2H).

Example 131 Methyl2-chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 18 (0.345 g, 1.091 mmol),3-chloro-4-methoxycarbonylphenylboronic acid (0.295 g, 1.37 mmol),potassium acetate (0.359 g, 3.65 mmol), dioxane (8 ml) andtetrakis(triphenylphosphine)palladium(0) (0.101 g, 0.087 mmol).Off-white solid (0.277 g, 56%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.91(d, J=3.3 Hz, 1H), 8.50 (d, J=8.6 Hz, 1H), 8.23 (s, 1H), 8.10 (d, J=8.2Hz, 1H), 8.03 (d, J=6.9 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.87 (m, 3H),7.38 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 3.97 (s, 3H).

Example 1322-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 131 (0.185 g, 0.412 mmol) in methanol (2 ml),lithium hydroxide (0.161 g, 3.84 mmol) in water (2 ml), THF (4 ml) wereadded and stirred at RT. After 12 h, pH was adjusted to ca.7 using 0.5NHCl and the solid precipitated was filtered, washed with ethyl acetateand petroleum ether and dried under vacuum to afford the title compoundas a pale brown solid (0.150 g, 84%).

Example 1332-Chloro-N-ethyl-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 43 replacing the example 13 with example 132 (0.100 g, 0.230mmol) and ethylamine hydrochloride. Off-white solid (0.020 g, 19%).M.P.: 197-199° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.92 (dd, J=4.2, 2.8Hz, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.51 (t, J=5.4 Hz, 1H), 8.44 (d, J=8.0Hz, 1H), 8.28 (d, J=1.4 Hz, 1H), 8.22 (m, 3H), 7.83 (d, J=11.4 Hz, 1H),7.56 (m, 2H), 6.26 (s, 2H), 3.28 (m, 2H), 1.14 (t, J=7.2 Hz, 3H).

Example 1342-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 102 using Example 132 (0.050 g, 0.115 mmol), thionyl chloride (2ml) and aqueous 25% ammonia (2 ml). Brown solid (0.015 g, 30%). M.P.:202-204° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.92 (d, J=4.1 Hz, 1H),8.70 (d, J=8.6 Hz, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.27 (s, 1H), 8.22 (m,3H), 7.96 (s, 1H), 7.83 (d, J=11.5 Hz, 1H), 7.68 (s, 1H), 7.60 (d, J=8.0Hz, 1H), 7.55 (dd, J=8.4, 4.3 Hz, 1H), 6.26 (s, 2H).

Example 135 Methyl2-fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 18 (0.350 g, 1.15 mmol),3-fluoro-4-methoxycarbonyl phenylboronic acid (0.276 g, 1.39 mmol),potassium acetate (0.365 g, 3.71 mmol), dioxane (8 ml) andtetrakis(triphenylphosphine)palladium(0) (0.103 g, 0.089 mmol). Palebrown solid (0.350 g, 70%). M.P.: 213-215° C.

Example 1362-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 135 (0.240 g, 0.605 mmol) in methanol (3 ml),lithium hydroxide (0.237 g, 5.64 mmol) in water (3 ml), THF (6 ml) wereadded and stirred at RT. After 12 h, pH was adjusted to ca 7 using 0.5NHCl and the solid precipitated was filtered, washed with ethyl acetateand petroleum ether and dried under vacuum to afford the title compoundas pale brown solid (0.110 g, 44%).

Example 1372-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 102 using Example 136 (0.080 g, 0.191 mmol), thionyl chloride (2ml) and aqueous 25% ammonia (2 ml). Pale brown solid (0.060 g, 75%).M.P.: 206-208° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.92 (d, J=3.2 Hz,1H), 8.71 (d, J=8.7 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.23 (t, J=9.2 Hz,2H), 8.19 (m, 2H), 7.83-7.73 (m, 4H), 7.54 (dd, J=8.2, 4.0 Hz, 1H), 6.26(s, 2H).

Example 1383-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 102 using Example 54 (0.100 g, 0.262 mmol), thionyl chloride (4ml) and aqueous 25% ammonia (4 ml). Brown solid (0.040 g, 40%). M.P.:263-265° C.

Example 1392,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

Example 130 (0.040 g. 0.096 mmol) was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as a brown solid (0.027 g, 43%). M.P.:272-275° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.02 (d, J=3.2 Hz, 1H),8.74 (d, J=8.8 Hz, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.26 (d, J=8.7 Hz, 1H),8.20 (d, J=13.6 Hz, 2H), 8.11 (m, 3H), 7.96 (m, 2H), 7.72 (dd, J=8.3,4.6 Hz, 1H), 6.28 (s, 2H).

Example 1402-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

The example 134 (0.035 g. 0.080 mmol) was dissolved in THF (2 ml), ethersaturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as a pale yellow solid (0.022 g, 59%). M.P.:269-272° C.

Example 1412-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

Example 137 (0.080 g. 0.192 mmol) was dissolved in THF (2 ml), ethersaturated with HCl (2 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was filtered, washed with ether and dried undervacuum to afford the title compound as a pale-brown solid (0.070 g,80%). M.P.: 258-260° C.

Example 1422-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol), intermediate 21(0.109 g, 0.422 mmol), potassium carbonate (0.155 g, 1.12 mmol), DMF (8ml), water (0.5 ml) and tetrakis (triphenyl-phosphine) palladium(0)(0.031 g, 0.027 mmol). Pale green solid (0.045 g, 34%). M.P.: 235-237°C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (d, J=2.9 Hz, 1H), 8.66 (d,J=8.7 Hz, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H), 8.07-8.00(m, 4H), 7.83 (m, 2H), 7.54 (m, 2H), 7.45 (s, 1H), 6.21 (s, 2H), 2.46(s, 3H).

Example 1436-((5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was obtained as a yellow solid (0.065 g, 29%) byfollowing the procedure described for example 1 using intermediate 14(0.20 g, 0.676 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.254 g, 0.856 mmol), potassium carbonate (0.310 g, 2.25 mmol), dioxane(4 ml), water (0.8 ml) and tetrakis (triphenylphosphine)palladium(0)(0.062 g, 0.054 mmol). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.25 (s, 1H),8.88 (dd, J=4.1, 1.4 Hz, 1H), 8.55 (s, 1H), 8.50 (d, J=8.7 Hz, 1H), 8.38(d, J=8.1, Hz, 1H), 8.23 (s, 1H), 8.01 (d, J=9.0, Hz, 2H), 7.85 (t,J=8.6, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H). MS (m/z): 328.12(M⁺+1).

Example 1446-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

Sodium hydride (0.014 g, 0.596 mmol) was added to a solution of example143 (0.130 g, 0.397 mmol) in DMF (3 ml) at 0° C. and stirred for 30 min.To this solution methyl iodide (0.113 g, 0.794 mmol) was added and thereaction mixture was warmed to RT. After 3 h, the reaction mixture waspoured into ice water and extracted with ethyl acetate, washed withbrine, dried over sodium sulphate and concentrated. The crude productwas purified by column chromatography with methanol: dichloromethane toafford the title compound as an off-white solid (0.080 g, 59%). ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.88 (d, J=2.8 Hz, 1H), 8.51 (s, 1H), 8.49(s, 1H), 8.38 (d, J=7.9 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J=8.8 Hz, 2H),7.82 (t, J=9.6 Hz, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.10 (s, 2H), 3.91(s, 3H). MS (m/z): 341.98 (M⁺+1).

Example 1456-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of example 143 (0.250 g, 0.763 mmol) in DMF (10 ml),cesium carbonate (0.496 g, 1.52 mmol) was added and stirred for 15 min.2-(2-bromoethoxy)tetrahydro-2H-pyran (0.638 g, 3.04 mmol) andtetrabutylammonium iodide (0.20 g, 2.16 mmol) were added and heated to80-85° C. for 12 h. The reaction was quenched by the addition of water,extracted with ethyl acetate, washed with brine, dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.195 g, 56%). ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.52 (s, 1H), 8.51 (d, J=8.8 Hz,1H), 8.37 (dd, J=8.4, 1.3 Hz, 1H), 8.22 (s, 1H), 8.01 (d, J=9.0 Hz, 2H),7.82 (dd, J=8.7, 2.7 Hz, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s,2H), 4.54 (t, J=2.9 Hz, 1H), 4.37 (m, 2H), 3.99 (m, 1H), 3.73 (m, 1H),3.55 (m, 1H), 1.63-1.30 (m, 6H).

Example 1462-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

To a solution of example 145 (0.190 g, 0.417 mmol) in methanol (2 ml)and water (2 ml), camphor sulphonic acid (0.968 g, 4.17 mmol) was addedand stirred for 1 h. The reaction was poured into ice water and the pHwas adjusted to ca 8 with sodium bicarbonate solution, extracted withethyl acetate, washed with brine, dried over sodium sulphate andconcentrated. The crude product was purified by recrystallisation fromisopropanol to afford the title compound as a light yellow solid (0.059g, 38%). M.P.: 179-178° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd,J=4.2, 1.6 Hz, 1H), 8.51 (d, J=8.7 Hz, 1H), 8.49 (s, 1H), 8.38 (dd,J=8.3, 1.3 Hz, 1H), 8.20 (s, 1H), 8.01 (d, J=8.0 Hz, 2H), 7.82 (dd,J=8.7, 1.7 Hz, 2H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.11 (s, 2H), 4.96 (t,J=5.3 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.79 (dd, J=10.8, 5.4 Hz, 2H). MS(m/z): 372.08 (M⁺+1).

Example 1476-((5-(1H-Pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as a yellow solid (0.110 g, 49%) byfollowing the procedure described for example 1 using intermediate 29(0.20 g, 0.678 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.255 g, 0.868 mmol), potassium carbonate (0.310 g, 2.24 mmol), dioxane(4 ml), water (0.8 ml) and tetrakis(triphenylphosphine)palladium(0)(0.062 g, 0.054 mmol). M.P.: 214-216° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 13.02 (s, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.56 (s, 1H), 8.35(dd, J=8.2, 1.1 Hz, 2H), 8.10 (s, 1H), 8.04-7.98 (m, 3H), 7.85 (dd,J=8.8, 1.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (dd, J=8.3, 4.2 Hz,1H), 5.69 (s, 2H). MS (m/z): 326.86 (M+).

Example 1486-((5-(1-Methyl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as an off-white solid (0.022 g, 27%) byfollowing the procedure described for example 144 using example 147(0.080 g, 0.245 mmol), sodium hydride (0.014 g, 0.367 mmol), methyliodide (0.069 g, 0.49 mmol) and DMF (2 ml). M.P.: 150-152° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.86 (s, 1H), 8.56 (s, 1H), 8.35 (d, J=8.1 Hz,1H), 8.29 (s, 1H), 8.04 (m, 4H), 7.84 (d, J=8.8 Hz, 1H), 7.56 (d, J=8.3Hz, 1H), 7.52 (dd, J=7.8, 4.2 Hz, 1H), 5.69 (s, 2H), 3.88 (s, 3H). MS(m/z): 341.14 (M⁺+1).

Example 1496-((5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as a yellow solid (0.300 g, 86%) byfollowing the procedure described for example 145 using example 147(0.250 g, 0.766 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.640 g,3.06 mmol), cesium carbonate (0.746 g, 2.29 mmol), tetrabutylammoniumiodide (0.20 g, 0.54 mmol) and DMF (10 ml).

Example 1502-(4-(3-(Quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

The title compound was prepared by following the procedure described forexample 146 using example 149 (0.200 g, 0.44 mmol), camphor sulphonicacid (1.02 g. 4.40 mmol), methanol (2 ml) and water (2 ml). Yellow solid(0.09 g, 55%). M.P.: 160-163° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.86(dd, J=4.0, 1.4 Hz, 1H), 8.55 (s, 1H), 8.35 (d, J=7.9 Hz, 1H), 8.30 (s,1H), 8.05 (m, 4H), 7.84 (dd, J=8.7, 1.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 1H),7.52 (dd, J=8.4, 4.2 Hz, 1H), 5.69 (s, 2H), 4.94 (t, J=5.2 Hz, 1H), 4.19(t, J=5.6 Hz, 2H), 3.77 (t, J=5.4 Hz, 2H). MS (m/z): 370.89 (M+).

Example 1512-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-ylamino)ethanol

To a solution of intermediate 14 (0.100 g, 0.338 mmol) and2-aminoethanol (0.041 g, 0.67 mmol) in ethanol (2.5 ml), sodiumcarbonate (0.071 g, 0.676 mmol) was added and heated to reflux. After 12h, the reaction was quenched by the addition of ice water, extractedwith ethyl acetate, washed with brine, dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane to afford the title compound as a yellowsolid (0.060 g, 55%). M.P.: 184-186° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.35 (dd, J=8.3, 0.9 Hz, 1H), 7.99(d, J=8.7 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.76 (dd,J=8.7, 2.0 Hz, 1H), 7.55 (t, J=4.5 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz,1H), 6.64 (d, J=9.1 Hz, 1H), 5.82 (s, 2H), 4.73 (t, J=5.4 Hz, 1H), 3.58(q, J=5.9 Hz, 2H), 3.45 (q, J=5.6 Hz, 2H). MS (m/z): 321.19 (M⁺+1).

Example 1526-((5-(1H-Imidazol-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of intermediate 14 (0.100 g, 0.338 mmol) and imidazole(0.100 g, 1.46 mmol) in DMF (3 ml), cesium fluoride (0.056 g, 0.368mmol) was added and heated to 130° C. After 12 h, the reaction wasquenched by the addition of ice water, extracted with ethyl acetate,washed with brine, dried over sodium sulphate and concentrated. Thecrude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as light brown solid (0.023g, 21%). M.P.: 227-230° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd,J=4.2, 1.7 Hz, 1H), 8.80 (d, J=8.9 Hz, 1H), 8.76 (s, 1H), 8.39 (dd,J=8.4, 0.9 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.7Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.84 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (dd,J=8.3, 4.2 Hz, 1H), 7.18 (s, 1H), 6.15 (s, 2H). MS (m/z): 327.91 (M+).

Example 1536-((5-(1-Propyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of Example 143 (0.100 g, 0.305 mmol) in DMF (4 ml), cesiumcarbonate (0.297 g, 0.913 mmol), tetrabutylammonium iodide (0.078 g,0.213 mmol) and 1-bromopropane (0.150 g, 1.22 mmol) were added andheated to 65° C. After 12 h, the reaction mixture was poured into icewater and extracted with ethyl acetate, washed with brine, dried oversodium sulphate and concentrated. The crude product was purified bycolumn chromatography with methanol: dichloromethane to afford the titlecompound as a greenish-yellow solid (0.045 g, 40%). M.P.: 128-130° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.53 (s,1H), 8.51 (d, J=8.8 Hz, 1H), 8.38 (dd, J=8.4, 1.8 Hz, 1H), 8.19 (s, 1H),8.01 (d, J=8.3 Hz, 1H), 7.99 (s, 1H), 7.82 (m, 2H), 7.53 (q, J=4.2 Hz,1H), 6.11 (s, 2H), 4.11 (t, J=6.9 Hz, 2H), 1.85 (m, 2H), 0.86 (t, J=7.3Hz, 3H). MS (m/z): 370.33 (M⁺+1).

Example 154 Ethyl2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)acetate

To a solution of example 143 (0.250 g, 0.763 mmol) in DMF (3 ml) cooledto 0° C., sodium hydride (0.0365 g, 0.916 mmol) was added and stirredfor 30 min., ethyl bromoacetate (0.153 g, 0.916 mmol) were added andwarmed to RT. After 12 h, the reaction mixture was poured into ice waterand extracted with ethyl acetate, washed with brine, dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as a yellow solid (0.225 g, 80%).

Example 1552-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)aceticacid

To a solution of Example 154 (0.085 g, 0.218 mmol) in methanol (1.4 ml),lithium hydroxide (0.026 g, 1.09 mmol) in water (0.36 ml) was added andstirred at RT. After 12 h, the pH was adjusted to 7-7.5 using 0.5N HCland the solid precipitated was filtered, washed with ethyl acetate andpetroleum ether and dried under to afford the title compound as a yellowsolid (0.034 g, 38%). M.P.: >270° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.87 (d, J=2.7 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.39 (m, 2H), 8.08 (s,1H), 8.00 (s, 1H), 7.99 (d, J=7.1 Hz, 1H), 7.82 (t, J=8.9 Hz, 2H), 7.52(q, J=4.1 Hz, 1H), 6.10 (s, 2H), 4.48 (s, 2H). MS (m/z): 385.87 (M+).

Example 156 tert-Butyl4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a solution of example 143 (0.100 g, 0.305 mmol) in DMF (2 ml) wascooled to 0° C., sodium hydride (0.0146 g, 0.366 mmol) was added andstirred for 30 min., tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate (0.093 g, 0.336 mmol) wereadded and heated to 80° C. After 12 h, the reaction mixture was pouredinto ice water and extracted with ethyl acetate, washed with brine,dried over sodium sulphate and concentrated. The crude product waspurified by column chromatography with methanol:dichloromethane toafford the title compound as a yellow solid (0.066 g, 42%). ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.88 (d, J=2.7 Hz, 1H), 8.60 (s, 1H), 8.52 (d,J=8.7 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 8.21 (s, 1H), 8.01 (s, 1H), 8.01(d, J=7.5 Hz, 1H), 7.82 (d, J=8.6 Hz, 2H), 7.53 (q, J=4.1 Hz, 1H), 6.11(s, 2H), 4.46 (m, 1H), 4.12 (m, 2H), 2.91 (m, 2H), 2.06 (m, 2H), 1.87(m, 2H), 1.41 (s, 9H).

Example 1576-((5-(1-(Piperidin-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of example 156 (0.063 g, 0.123 mmol) in dichloromethane (1ml) was cooled to 0° C., TFA (0.356 g, 2.47 mmol) was added and warmedto RT. After 12 h, the reaction mixture was poured in ice water and pHwas adjusted to 10-11 with 10% NaOH solution and extracted with ethylacetate, washed with brine, dried over sodium sulphate and concentratedto afford the title compound as an off-white solid (0.021 g, 42%). M.P.:188-191° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.6 Hz,1H), 8.55 (s, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.38 (d, J=7.8 Hz, 1H), 8.20(s, 1H), 8.01 (s, 1H), 8.01 (m, 2H), 7.82 (m, 2H), 7.53 (q, J=4.2 Hz,1H), 6.11 (s, 2H), 4.29 (m, 1H), 3.07 (m, 2H), 2.63 (m, 2H), 1.99 (m,2H), 1.86 (m, 2H). MS (m/z): 411.28 (M⁺+1).

Example 158(R)-1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

The title compound was prepared by following the procedure described forexample 152 using intermediate 14 (0.100 g, 0.338 mmol),(R)-3-hydroxypyrrolidine (0.044 g, 0.507 mmol), cesium fluoride (0.102g, 0.676 mmoles) and DMF (3 ml). Brown solid (0.040 g, 34%). M.P.:167-169° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz,1H), 8.36 (dd, J=8.4, 1.0 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.99 (d,J=8.6 Hz, 1H), 7.93 (d, J=1.5 Hz, 1H), 7.77 (dd, J=8.7, 2.0 Hz, 1H),7.53 (q, J=4.2 Hz, 1H), 6. 66 (d, J=9.2 Hz, 1H), 5.86 (s, 2H), 5.01 (s,1H), 4.40 (s, 1H), 3.60 (m, 4H), 2.04-1.92 (m, 2H). MS (m/z): 346.95(M+).

Example 1593-(4-Fluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine

The title compound was prepared by following the procedure described forexample 1 using intermediate 15 (0.500 g, 1.90 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.716 g, 2.43 mmol), potassium carbonate (0.874 g, 6.33 mmol), dioxane(11 ml), water (2.2 ml) and tetrakis(triphenylphosphine)palladium(0)(0.175 g, 0.152 mmol). Yellow solid (0.270 g, 48%). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 13.26 (s, 1H), 8.55 (s, 1H), 8.48 (d, J=8.7 Hz, 1H),8.23 (s, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.53 (dd, J=8.5, 6.4 Hz, 2H), 7.18(t, J=8.9 Hz, 2H), 5.89 (s, 2H).

Example 1603-(4-Fluorobenzyl)-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine

The title compound was prepared by following the procedure described forexample 145 using example 159 (0.270 g, 0.917 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.766 g, 3.66 mmol), cesium carbonate (0.894 g,2.75 mmol), tetrabutylammonium iodide (0.237 g, 0.624 mmol) and DMF (12ml). Brown solid (0.150 g, 38%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.52(s, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.21 (s, 1H), 7.80 (d, J=8.6 Hz, 1H),7.50 (m, 2H), 7.20 (m, 2H), 5.89 (s, 2H), 4.56 (t, J=3.4 Hz, 1H), 4.38(m, 2H), 3.98 (m, 1H), 3.80 (m, 1H), 3.57 (m, 1H), 3.38 (m, 1H),1.66-1.05 (m, 6H).

Example 1612-(4-(3-(4-Fluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

The title compound was prepared by following the procedure described forexample 145 using example 160 (0.150 g, 0.355 mmol), camphor sulphonicacid (0.824 g. 3.55 mmol), methanol (2 ml) and water (2 ml). Brown solid(0.070 g, 58%). M.P.: 204-206° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.49(s, 1H), 8.49 (d, J=9.7 Hz, 1H), 8.20 (s, 1H), 7.80 (d, J=8.7 Hz, 1H),7.51 (dd, J=8.7, 5.5 Hz, 2H), 7.20 (t, J=8.9 Hz, 2H), 5.89 (s, 2H), 4.96(t, J=5.3 Hz, 1H), 4.23 (t, J=5.5 Hz, 2H), 3.80 (q, J=5.4 Hz, 2H). MS(m/z): 339.25 (M⁺+1).

Example 1626-(1-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline

The title compound was prepared by following the procedure described forintermediate 14 using intermediate 31 (0.290 g, 0.877 mmol), acetic acid(1.8 ml), sodium nitrite (0.072 g, 1.05 mmol) and water (0.4 ml). Brownsolid (0.250 g, 84%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 13.25 (s, 1H),8.87 (dd, J=4.0, 1.4 Hz, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.39 (d, J=7.6 Hz,1H), 8.09 (d, J=1.5 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.88 (dd, J=8.8,1.9 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.64-7.46 (m, 3H), 6.60 (q, J=7.1Hz, 1H), 2.22 (d, J=7.1 Hz, 3H).

Example 1636-(1-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)ethyl)quinoline

The title compound was prepared by following the procedure described forexample 145 using example 162 (0.190 g, 0.556 mmol),2-(2-bromoethoxy)tetrahydro-2H-pyran (0.465 g, 2.22 mmol), cesiumcarbonate (0.550 g, 1.69 mmol), tetrabutylammonium iodide (0.143 g,0.387 mmol) and DMF (7 ml). Yellow solid (0.138 g, 46%). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.87 (dd, J=4.1, 1.6 Hz, 1H), 8.50 (s, 1H), 8.49 (d,J=8.7 Hz, 1H), 8.38 (d, J=8.1 Hz, 1H), 8.19 (s, 1H), 8.06 (s, 1H), 7.99(d, J=8.7 Hz, 1H), 7.86 (d J=8.7 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.52(q, J=4.2 Hz, 1H), 6.59 (q, J=7.0 Hz, 1H), 4.53 (t, J=3.0 Hz, 1H), 4.48(m, 2H), 3.99 (m, 1H), 3.78 (m, 1H), 3.56 (m, 1H), 2.23 (d, J=7.2 Hz,3H), 1.59-1.20 (m, 7H).

Example 1642-(4-(3-(1-(Quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

The title compound was prepared by following the procedure described forexample 146 using example 163 (0.130 g, 0.276 mmol), camphor sulphonicacid (0.643 g. 2.76 mmol), methanol (2 ml) and water (2 ml). Yellowsolid (0.030 g, 28%). M.P.: 188-191° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.87 (d, J=2.6 Hz, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.47 (s, 1H), 8.39(d, J=8.1 Hz, 1H), 8.18 (s, 1H), 8.08 (dd, J=0.7 Hz, 1H), 8.00 (d, J=8.7Hz, 1H), 7.87 (dd, J=8.8, 1.9 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.52 (q,J=4.2 Hz, 1H), 6.60 (q, J=6.8 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.21 (t,J=5.4 Hz, 2H), 3.78 (q, J=5.4 Hz, 2H), 2.22 (d, J=7.2 Hz, 3H). MS (m/z):385.87 (M+).

Example 1652-(4-(3-(2-Chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

To a solution of Example 213 (0.160 g, 0.461 mmol) in DMF (7 ml), cesiumcarbonate (0.449 g, 1.38 mmol) was added and stirred for 15 min.2-(2-bromoethoxy)tetrahydro-2H-pyran (0.385 g, 1.84 mmol) andtetrabutylammonium iodide (0.137 g, 0.368 mmol) were added and heated to80-85° C. for 12 h. The reaction was quenched by the addition of water,extracted with ethyl acetate, washed with brine, dried over sodiumsulphate and concentrated to give the crude product (0.220 g). To asolution of above crude product (0.210 g, 0.442 mmol) in methanol (2 ml)and water (2 ml), camphor sulphonic acid (1.027 g. 4.42 mmol) was addedand stirred for 1 h. The reaction was poured into ice water and the pHwas adjusted to ca. 8 by sodium bicarbonate solution, extracted withethyl acetate, washed with brine, dried over sodium sulphate andconcentrated to afford the title compound as a yellow solid (0.045 g,26%). M.P.: 143-145° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.47 (d, J=8.7Hz, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.61 (dt,J=9.1, 4.8 Hz, 1H), 7.45 (dt, J=9.2, 4.3 Hz, 1H), 6.01 (s, 2H), 4.99 (t,J=5.2 Hz, 1H), 4.22 (t, J=5.3 Hz, 2H), 3.79 (q, J=5.2 Hz, 2H). MS (m/z):390.70 (M+).

Example 166 tert-Butyl4-(4-(3-(2-chloro-3,6-difluorobenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

The title compound was prepared as a yellow solid (0.250 g, 41%) byfollowing the procedure described for example 156 using example 213(0.400 g, 1.15 mmol), sodium hydride (0.060 g, 1.49 mmol), tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate (0.400 g, 1.43 mmol) andDMF (2 ml).

Example 1673-(2-Chloro-3,6-difluorobenzyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridinehydrochloride

To a solution of Example 166 (0.240 g, 0.453 mmol) in dichloromethane (3ml) cooled to 0° C., TFA (0.1 ml) was added and warmed to RT. After 2 h,the reaction mixture was poured in ice water and pH was adjusted to callwith 10% NaOH solution and extracted with ethyl acetate, washed withbrine, dried over sodium sulphate and concentrated. The residue wasdissolved in THF (1 ml), ether saturated with HCl (1 ml) was added at 0°C. and stirred for 15 min. The precipitate formed was filtered andwashed with ether and dried under vacuum to afford the title compound asan off-white solid (0.090 g, 43%). M.P.: 85-87° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.48 (d, J=1.5 Hz, 1H), 8.45 (s, 1H), 8.09 (s, 1H),7.79 (d, J=8.7 Hz, 1H), 7.60 (dt, J=13.8, 4.8 Hz, 1H), 7.45 (dt, J=13.4,4.2 Hz, 1H), 6.01 (s, 2H), 4.29 (m, 1H), 3.07 (d, J=12.4 Hz, 2H), 2.63(m, 2H), 1.98 (m, 2H), 1.85 (m, 2H). MS (m/z): 429.69 (M⁺-HCl).

Example 1686-((5-(3-Methyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as a yellow solid (0.030 g, 15%) bySuzuki coupling of tert-butyl3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(0.227 g, 0.634 mmol) with intermediate 14 (0.150 g, 0.507 mmol)following the procedure described for example 1 using potassiumcarbonate (0.233 g, 1.68 mmol), dioxan (3 ml), water (0.6 ml) andtetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol)followed by deprotection of the carbamate as described under 157. M.P.:136-137° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.90 (s, 1H), 8.88 (d,J=3.1 Hz, 1H), 8.66 (d, J=8.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.30 (s,1H), 8.21 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.98(d, J=8.4 Hz, 1H), 7.85 (d, J=8.5 Hz, 2H), 7.53 (q, J=4.2 Hz, 1H), 6.25(s, 2H), 2.52 (s, 3H).

Example 1696-((5-(1H-Indol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.150 g, 0.507 mmol),6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.154 g,0.634 mmol), potassium carbonate (0.233 g, 1.68 mmol), dioxane (3 ml),water (0.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.046 g,0.04052 mmol). Light green solid (0.025 g, 13%). M.P.: 120-122° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.30 (s, 1H), 8.88 (dd, J=4.2, 1.6Hz, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.45 (s, 1H), 8.39 (d, J=8.3 Hz, 1H),8.13 (d, J=8.9 Hz, 1H), 8.04 (m, 3H), 7.84 (dd, J=8.8, 1.8 Hz, 1H), 7.53(m, 2H), 7.42 (t, J=2.7 Hz, 1H), 6.56 (s, 1H), 6.20 (s, 2H).

Example 1706-((5-(1H-Indol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was obtained as an off-white solid (0.015 g, 8%) byfollowing the procedure described for example 1 using intermediate 14(0.150 g, 0.507 mmol), 1H-indole-6-yl boronic acid (0.102 g, 0.634mmol), potassium carbonate (0.233 g, 1.68 mmol), dioxane (3 ml), water(0.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052mmol). M.P.: 143-145° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.38 (s,1H), 8.88 (dd, J=4.0, 1.5 Hz, 1H), 8.58 (d, J=8.8 Hz, 1H), 8.38 (d,J=8.7 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 8.04 (m, 2H), 7.92(dd, J=8.4, 1.4 Hz, 1H), 7.86 (dd, J=8.8, 1.9 Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.54 (q, J=4.2 Hz, 1H), 7.49 (d, J=2.6 Hz, 1H), 6.49 (s, 1H),6.20 (s, 2H).

Example 1716-((5-(2-Chloropyridin-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as an off-white solid (0.020 g, 11%) byfollowing the procedure described for example 1 using intermediate 14(0.150 g, 0.507 mmol), 2-chloropyridine-4-boronic acid (0.099 g, 0.634mmol), potassium carbonate (0.233 g, 1.68 mmol), dioxane (3 ml), water(0.6 ml) and tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052mmol). M.P.: 197-199° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd,J=4.1, 1.5 Hz, 1H), 8.79 (d, J=8.7 Hz, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.37(d, J=8.4 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 8.25 (dd,J=5.2, 1.5 Hz, 1H), 8.04 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.83 (dd,J=8.7, 1.9 Hz, 1H), 7.54 (q, J=4.2 Hz, 1H), 6.25 (s, 2H).

Example 1726-((5-(3-Methyl-1H-indazol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as a yellow solid (0.050 g, 25%) byfollowing the procedure described for example 1 using intermediate 14(0.150 g, 0.507 mmol), tert-butyl3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-methyl-1H-indazole-1-carboxylate(0.227 g, 0.634 mmol), potassium carbonate (0.233 g, 1.68 mmol), dioxane(3 ml), water (0.6 ml) and tetrakis(triphenylphosphine)palladium(0)(0.046 g, 0.04052 mmol) followed by the procedure described in example157. M.P.: 246-249° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 12.82 (s, 1H),8.88 (d, J=2.6 Hz, 1H), 8.62 (d, J=8.8 Hz, 1H), 8.59 (s, 1H), 8.38 (d,J=8.3 Hz, 1H), 8.30 (d, J=9.1 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.03 (s,1H), 8.01 (d, J=9.9 Hz, 1H), 7.84 (dd, J=8.6, 1.5 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.53 (q, J=4.2 Hz, 1H), 6.21 (s, 2H), 2.56 (s, 3H).

Example 1736-((5-(Pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.150 g, 0.507 mmol),pyridine-3-boronic acid (0.079 g, 0.649 mmol), potassium carbonate(0.233 g, 1.68 mmol), dioxane (3 ml), water (0.6 ml) andtetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.04052 mmol)followed by the procedure described in example 157. Yellow solid (0.040g, 24%). M.P.: 208-210° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd,J=4.1, 1.7 Hz, 1H), 8.77 (m, 3H), 8.38 (dd, J=8.4, 0.9 Hz, 1H), 8.26 (d,J=8.7 Hz, 1H), 8.21 (m, 2H), 8.04 (d, J=1.5 Hz, 1H), 8.02 (d, J=8.7 Hz,1H), 7.85 (dd, J=8.7, 2.0 Hz, 1H), 7.53 (q, J=4.2 Hz, 1H), 6.24 (s, 2H).

Example 174(S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by alkylation of example 143 (0.300 g,0.916 mmol) with (R)-tert-butyl3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (0.291 g, 1.09 mmol)following the procedure described under example 156 using sodium hydride(0.026 g, 1.09 mmol) and DMF (6 ml) followed by deprotection of thecarbamate using the procedure described for 157. Yellow solid (0.100 g,44%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.1, 1.4 Hz, 1H),8.59 (s, 1H), 8.52 (d, J=8.8 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.22 (s,1H), 8.01 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.82 (m, 2H), 7.53 (dd,J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H), 4.98 (m, 1H), 3.26-2.96 (m, 5H),2.28-2.11 (m, 2H).

Example 175(S)-6-((5-(1-(Pyrrolidin-3-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinolinehydrochloride

Example 174 (0.100 g, 0.25 mmol), was dissolved in THF (1 ml), ethersaturated with HCl (1 ml) was added at 0° C. and stirred for 15 min. Theprecipitate formed was washed with ether and dried under vacuum toafford the title compound as a yellow solid (0.070 g, 65%). M.P.:117-121° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.58 (s, 1H), 9.45 (s,1H), 9.12 (d, J=3.7 Hz, 1H), 8.87 (d, J=8.1 Hz, 1H), 8.73 (s, 1H), 8.56(d, J=8.7 Hz, 1H), 8.30 (s, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.21 (s, 1H),8.07 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 6.18 (s, 2H), 5.27 (t,J=3.3 Hz, 1H), 3.69-3.34 (m, 4H), 2.43-2.30 (s, 2H).

Example 1764-(2-(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethyl)morpholinehydrochloride

The title compound was prepared by following the procedure described forexample 156 using example 143 (0.150 g, 0.458 mmol), sodium hydride(0.022 g, 0.55 mmol), (4-(2-chloroethyl)morpholine (0.115 g, 1.00 mmol)and DMF (3 ml) followed by using the procedure described for 175. Yellowsolid (0.080 g, 36%). M.P.: 118-120° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 11.08 (s, 1H), 9.06 (d, J=3.7 Hz, 1H), 8.74 (d, J=8.3 Hz, 1H),8.65 (s, 1H), 8.57 (d, J=8.6 Hz, 1H), 8.31 (s, 1H), 8.18 (d, J=8.8 Hz,1H), 8.13 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.78(dd, J=7.7, 4.4 Hz, 1H), 6.16 (s, 2H), 4.72 (t, J=6.6 Hz, 1H), 3.97(br.s, 2H), 3.77 (t, J=11.5 Hz, 2H), 3.65 (t, J=11.5 Hz, 2H), 3.42 (d,J=11.6 Hz, 2H), 3.17 (m, 2H).

Example 1776-((5-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared as a yellow solid (0.130 g, 52%) byfollowing the procedure described for example 156 using example 143(0.200 g, 0.610 mmol), cesium carbonate (0.596 g, 1.83 mmol),tetrahydro-2H-pyran-4-yl methanesulfonate (0.220 g, 1.22 mmol) and DMF(6 ml). M.P.: 182-184° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd,J=4.2, 1.7 Hz, 1H), 8.59 (s, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.38 (d, J=8.2Hz, 1H), 8.21 (s, 1H), 8.01 (m, 2H), 7.82 (m, 2H), 7.53 (dd, J=8.3, 4.1Hz, 1H), 6.11 (s, 2H), 4.52 (m, 1H), 3.99 (m, 2H), 3.51 (dt, J=11.2, 3.0Hz, 2H), 2.02 (m, 4H).

Example 1786-((5-(1-(2-Hydroxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline1-oxide: T

To a solution of example 146 (0.100 g, 0.269 mmol) in acetic acid (1ml), hydrogen peroxide solution (50%, 1 ml) and heated to 100° C. After12 h, the mixture was concentrated, extracted with chloroform, washedwith brine, dried over sodium sulphate and concentrated. The crudeproduct was purified by column chromatography using dichloromethane:methanol to afford the title compound as an off-white solid (0.015 g,14%). M.P.: 222-224° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.58-8.48 (m,4H), 8.19 (s, 1H), 8.08 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.85 (dd,J=9.0, 1.8 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.4, 6.0 Hz,1H), 6.12 (s, 2H), 4.95 (t, J=5.2 Hz, 1H), 4.22 (t, J=5.5 Hz, 2H), 3.77(q, J=5.5 Hz, 2H).

Example 1796-((5-(1,3-dimethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),1,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(0.0117 g, 0.432 mmol), potassium carbonate (0.146 g, 1.05 mmol),dioxane (3 ml), water (0.6 ml) andtetrakis(triphenylphosphine)palladium(0). (0.061 g, 45%) Yellow solid(0.061 g, 45%). M.P.: 159-163° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88(dd, J=4.0, 1.6 Hz, 1H), 8.69 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.38 (d,J=8.0 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.05-8.01 (m, 3H), 7.85 (m, 2H),7.54 (dd, J=8.3, 4.1 Hz, 1H), 6.24 (s, 2H).

Example 1805-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyrimidin-2-amine

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-amino-5-pyrimidineboronic acid (0.058 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Yellow solid (0.020g, 16%). M.P.: 244-246° C. MS (m/z): 354.72 (M+).

Example 181 tert-Butyl3-ethyl-6-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-indazole-1-carboxylate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol), tert-butyl3-ethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate(0.157 g, 0.422 mmol), potassium carbonate (0.156 g, 0.027 mmol),dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Off-white solid(0.070 g, 51%). M.P.: 185-188° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.93(s, 1H), 8.91 (dd, J=4.2, 1.5 Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.20 (d,J=8.3 Hz, 1H), 8.11 (m, 2H), 7.98 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.90(dd, J=8.8, 1.8 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.41 (dd, J=8.3, 4.3Hz, 1H), 6.16 (s, 2H), 3.10 (q, J=7.6 Hz, 2H), 1.74 (s, 9H), 1.48 (t,J=7.6 Hz, 3H).

Example 1824-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophene-2-carbaldehyde

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-formylthiophene-4-boronic acid (0.032 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Brown solid (0.060 g,7%). M.P.: 195-197° C. MS (m/z): 372.08 (M+).

Example 1836-((5-(2-Methoxypyrimidin-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-methoxypyrimidine-5-boronic acid (0.065 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Yellow solid (0.060g, 48%). M.P.: 201-203° C. MS (m/z): 369.98 (M+).

Example 1846-((5-(Benzo[d][1,3]dioxol-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),benzo[d][1,3]dioxol-5-ylboronic acid (0.056 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Off-white solid(0.070 g, 54%). M.P.: 179-181° C. MS (m/z): 382.16 (M⁺+1).

Example 1856-((5-(2,3-Dihydrobenzofuran-5-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2,3-dihydrobenzofuran-5-ylboronic acid (0.055 g, 0.422 mmol), potassiumcarbonate (0.156 g, 0.027 mmol), dioxane (2 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Pale brown solid(0.065 g, 50%). M.P.: 131-133° C. MS (m/z): 379.92 (M⁺).

Example 1865-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridin-2-amine

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.096 g,0.439 mmol), potassium carbonate (0.156 g, 0.027 mmol), dioxane (2 ml),water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g,0.067 mmol) under microwave irradiation (100 W, 100° C.) for 20 min.Yellow solid (0.050 g, 42%). M.P.: 194-197° C. MS (m/z): 353.95 (M⁺).

Example 1876-((5-(1-(2-fluoroethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

Methane sulphonyl chloride (0.069 g, 0.605 mmol) was added at 0° C. to asolution of example 146 (0.150 g, 0.403 mmol) and triethylamine (0.122g, 1.21 mmol) in dichloromethane (3 ml) and warmed to RT. After 1 h, themixture was diluted and washed with sodium bicarbonate solution, washedwith brine, dried over sodium sulphate and concentrated. To the residue,cesium fluoride (0.270 g, 1.77 mmol) and tert-butanol (2 ml) were addedand heated to 70° C. for 12 h. The reaction mixture was poured in water,extracted with ethyl acetate, washed with brine, dried over sodiumsulphate and concentrated. The crude product was purified by columnchromatography using dichloromethane: methanol to afford the titlecompound as an off-white solid (0.015 g, 10%). M.P.: 168-170° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.57 (s, 1H),8.53 (d, J=8.7 Hz, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.26 (s, 1H), 8.01 (d,J=8.1 Hz, 1H), 7.99 (s, 1H), 7.83 (m, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H),6.11 (s, 2H), 4.88 (dt, J=47.1, 4.5 Hz, 2H), 4.56 (dt, J=27.7, 4.8 Hz,2H) MS (m/z): 374.1 (M⁺+1).

Example 188(4-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)thiophen-2-yl)methanol

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methanol(0.066 g, 0.475 mmol), potassium carbonate (0.156 g, 0.027 mmol),dioxane (2 ml), water (0.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.067 mmol) under microwave irradiation (100 W,100° C.) for 20 min. Yellow solid (0.080 g, 63%). M.P.: 188-191° C. MS(m/z): 373.95 (M+).

Example 1896-(2-(5-(1-(2-(Tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 17 (0.100 g, 0.307 mmol),1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.126 g, 0.394 mmol), potassium carbonate (0.133 g, 0.963 mmol),dioxane (2.5 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol). Yellowliquid (0.065 g, 44%). ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.85 (d, J=2.8Hz, 1H), 8.47 (d, J=8.7 Hz, 1H), 8.37 (d, J=7.9 Hz, 1H), 8.22 (s, 1H),7.95 (d, J=1.7 Hz, 1H), 7.90 (s, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.69 (d,J=8.7 Hz, 1H), 7.53 (m, 1H), 4.46 (m, 1H), 4.27 (m, 2H), 3.88 (m, 1H),3.69 (m, 1H), 3.47 (m, 1H), 3.26 (m, 1H), 1.63-1.30 (m, 6H).

Example 1902-(4-(3-(2-(Quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanol

The title compound was prepared by following the procedure described forexample 146 from example 189 (0.050 g, 0.104 mmol), camphor sulphonicacid (0.121 g. 0.521 mmol), methanol (0.5 ml) and water (0.5 ml). Brownsolid (0.031 g, 74%). M.P.: 95-98° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.85 (d, J=2.8 Hz, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.40 (d, J=7.9 Hz, 1H),8.22 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.91 (d, J=8.9 Hz, 1H), 7.85 (s,1H), 7.68 (d, J=8.7 Hz, 1H), 7.53 (m, 2H), 4.87 (t, J=5.3 Hz, 1H), 4.11(t, J=5.4 Hz, 2H), 3.70 (q, J=5.4 Hz, 2H), 2.46 (s, 6H).

Example 1916-((5-(3-ethyl-1H-indazol-6-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of Example 181 (0.050 g, 0.099 mmol) in dichloromethane (1ml) cooled to 0° C., TFA (0.5 ml) was added and warmed to RT. After 2 h,the reaction mixture was poured in ice water and pH was adjusted to ca.11 with 10% NaOH solution and extracted with ethyl acetate, washed withbrine, dried over sodium sulphate and concentrated to afford the titlecompound as a yellow solid (0.023 g, 61%). M.P.: 211-213° C. MS (m/z):406.08 (M⁺).

Example 1926-(2-(5-(1H-Pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)propan-2-yl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 17 (0.20 g, 0.615 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.231 g, 0.788 mmol), potassium carbonate (0.266 g, 1.92 mmol), dioxane(5 ml), water (1 ml) and tetrakis(triphenylphosphine)palladium(0) (0.057g, 0.049 mmol). Yellow solid (0.075 g, 34%). M.P.: 218-220° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 13.02 (s, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H),8.56 (s, 1H), 8.35 (dd, J=8.2, 1.1 Hz, 2H), 8.10 (s, 1H), 8.04-7.98 (m,3H), 7.85 (dd, J=8.8, 1.9 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.52 (dd,J=8.3, 4.2 Hz, 1H), 5.69 (s, 2H). MS (m/z): 359.89 (M⁺).

Example 1936-((5-(4-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),4-methyl-2-thiopheneboronic acid (0.061 g, 0.432 mmol), potassiumcarbonate (0.146 g, 1.058 mmol), dioxane (2.5 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Brown solid (0.048 g,40%). M.P.: 153-156° C. MS (m/z): 357.85 (M+).

Example 1946-((5-(5-Methylthiophen-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),5-methyl-2-thiopheneboronic acid (0.060 g, 0.422 mmol), potassiumcarbonate (0.156 g, 1.12 mmol), dioxane (2.5 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Off-white solid(0.035 g, 29%). M.P.: 154-156° C. MS (m/z): 357.85 (M+).

Example 1954-(5-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)pyridin-2-yl)morpholine

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),6-morpholinopyridine-3-boronic acid (0.088 g, 0.422 mmol), potassiumcarbonate (0.156 g, 1.12 mmol), dioxane (2.5 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol) undermicrowave irradiation (100 W, 100° C.) for 20 min. Yellow solid (0.045g, 31%). M.P.: 183-185° C. MS (m/z): 423.93 (M+).

Example 1966-((5-(6-(Piperidin-1-yl)pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol),2-(piperidin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.122 g, 0.422 mmol), potassium carbonate (0.156 g, 1.12 mmol), dioxane(2.5 ml), water (0.5 ml) and tetrakis (triphenylphosphine)palladium(0)(0.031 g, 0.027 mmol) under microwave irradiation (100 W, 100° C.) for20 min. Brown solid (0.090 g, 63%). M.P.: 133-135° C. MS (m/z): 422.18(M⁺+1).

Example 1976-((5-(1-Ethyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 144 from example 143 (0.130 g, 0.397 mmol), sodium hydride(0.014 g, 0.596 mmol), ethyl iodide (0.123 g, 0.794 mmol) and DMF (3ml). Yellow solid (0.065 g, 46%). M.P.: 132-134° C. MS (m/z): 356.03(M⁺+1).

Example 1986-((5-(1-Isopropyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 144 from example 143 (0.130 g, 0.397 mmol), sodium hydride(0.014 g, 0.596 mmol), 2-bromopropane (0.097 g, 0.794 mmol) and DMF (3ml). Off-white solid (0.050 g, 34%). M.P.: 126-128° C. MS (m/z): 370.24(M⁺+1).

Example 1996-((5-(1-Isobutyl-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 144 from example 143 (0.130 g, 0.397 mmol), sodium hydride(0.014 g, 0.596 mmol), 1-bromo-2-methylpropane (0.108 g, 0.794 mmol) andDMF (3 ml). Pale green solid (0.070 g, 46%). M.P.: 160-163° C. MS (m/z):384.10 (M⁺+1).

Example 2001-(Pyrrolidin-1-yl)-2-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-1H-pyrazol-1-yl)ethanone

To a solution of example 155 (0.056 g, 0.145 mmol) in DMF (0.5 ml)N-ethyldiisopropylamine (0.018 g, 0.145 mmol) and HATU (0.055 g, 0.145mmol) were added and stirred for 5 min. Pyrrolidine (0.020 g, 0.290mmol) was added at RT and the reaction mixture was stirred for 12 h. Tothe reaction mixture water was added and extracted with ethyl acetate,dried over sodium sulphate and concentrated under reduced pressure. Thecrude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.010 g,16%). M.P.: 136-138° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.87 (dd,J=2.7 Hz, 1H), 8.52 (d, J=8.7 Hz, 1H), 8.45 (s, 1H), 8.37 (d, J=7.7 Hz,1H), 8.20 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.99 (s, 1H), 7.83 (m, 2H),7.52 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H), 5.11 (s, 2H), 3.52 (t, J=6.7Hz, 2H), 3.33 (m, 2H), 1.93-1.77 (m, 4H).

Example 2016-((5-(1-(2-Methoxyethyl)-1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 144 from example 143 (0.130 g, 0.397 mmol), sodium hydride(0.014 g, 0.596 mmol), 2-bromoethyl methyl ether (0.110 g, 0.794 mmol)and DMF (3 ml). Pale yellow solid (0.050 g, 33%). M.P.: 162-164° C.¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.90 (d, J=3.5 Hz, 1H), 8.30 (d, J=8.6Hz, 1H), 8.13 (m, 4H), 7.89 (s, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.54 (d,J=8.7 Hz, 1H), 7.41 (dd, J=8.3, 4.2 Hz, 1H), 6.07 (s, 2H), 4.38 (t,J=5.0 Hz, 2H), 3.81 (t, J=5.1 Hz, 2H), 3.36 (s, 3H).

Example 202N-Phenyl-3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-amine

To a solution of intermediate 14 (0.10 g, 0.338 mmol) and aniline (0.047g, 0.507 mmol) in o-xylene (0.8 ml), sodium tert-butoxide (0.038 g,0.405 mmol), triphenylphosphine (0.008 g, 0.033 mmol) and palladiumacetate (0.003 g, 0.169 mmol) were added and degassed for 30 min. andthe reaction mixture was heated to 120° C. for 4 h. The reaction mixturewas filtered through celite and washed with ethyl acetate, dried oversodium sulphate and concentrated under reduced pressure. The crudeproduct was purified by column chromatography with methanol:dichloromethane to afford the title compound as a brown solid (0.030 g,25%). M.P.: 237-239° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.72 (s, 1H),8.87 (d, J=3.9 Hz, 1H), 8.36 (d, J=8.6 Hz, 1H), 8.19 (d, J=9.0 Hz, 1H),8.00 (s, 1H), 7.98 (d, J=8.1 Hz, 1H), 7.73 (m, 3H), 7.53 (dd, J=8.0, 4.2Hz, 1H), 7.26 (m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.90 (d, J=9.0 Hz, 1H),5.98 (s, 2H).

Example 2036-((5-Phenoxy-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

To a solution of intermediate 14 (0.10 g, 0.338 mmol) and phenol (0.031g, 0.338 mmol) in N-methyl pyrrolidone (0.7 ml), potassium tert-butoxide(0.045 g, 0.405 mmol) was added and the reaction mixture was heated to80° C. for 12 h. The reaction mixture was quenched with water, extractedwith ethyl acetate, dried over sodium sulphate and concentrated underreduced pressure. The crude product was purified by columnchromatography with methanol: dichloromethane to afford the titlecompound as an off-white solid (0.040 g, 33%). M.P.: 225-227° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.91 (d, J=2.9 Hz, 1H), 8.29 (d, J=8.8 Hz,1H), 8.07 (d, J=8.1 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.76 (s, 1H), 7.67(dd, J=8.6, 1.4 Hz, 1H), 7.47 (m, 3H), 7.33 (t, J=7.4 Hz, 1H), 7.16 (d,J=8.0 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 5.80 (s, 2H).

Example 204 Methyl2-fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoate

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.250 g, 0.845 mmol),4-fluoro-3-methoxycarbonylphenylboronic acid pinacol ester (0.294 g,0.422 mmol), potassium acetate (0.276 g, 2.81 mmol), dioxane (4 ml) andtetrakis(triphenylphosphine)palladium(0) (0.050 g, 0.042 mmol).Off-white solid (0.080 g, 23%).

Example 2052-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzoicacid

To a solution of Example 204 (0.080 g, 0.193 mmol) in methanol (1 ml),lithium hydroxide (0.075 g, 1.80 mmol) in water (1 ml) and THF (2 ml)were added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using0.5N HCl and the solid precipitated was filtered, washed with ethylacetate and petroleum ether and dried under vacuum to afford the titlecompound as an off-white solid (0.060 g, 78%). The acid was used withoutfurther purification in the next step.

Example 2062-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

To Example 205 (0.060 g, 0.149 mmol), thionyl chloride (0.8 ml) wasadded and refluxed for 3 h. The excess thionyl chloride was removed;aqueous 25% ammonia (0.8 ml) was added to the residue at 0° C. andstirred for 15 min. The precipitate formed was washed with sodiumbicarbonate solution and vacuum dried to afford title compound as anoff-white solid (0.020 g, 34%). M.P.: 262-264° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.87 (d, J=2.7 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.50(d, J=6.7 Hz, 1H), 8.39 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.04(s, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.89 (s, 1H), 7.83 (d, J=8.7 Hz, 1H),7.78 (s, 1H), 7.53 (dd, J=8.2, 3.9 Hz, 1H), 7.49 (d, J=9.7 Hz, 1H), 6.21(s, 2H).

Example 2072-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 34 (0.065 g, 0.196 mmol), intermediate 35(0.070 g, 0.245 mmol), potassium carbonate (0.090 g, 0.654 mmol),dioxane (2 ml), water (0.3 ml) andtetrakis(triphenylphosphine)palladium(0) (0.018 g, 0.015 mmol) undermicrowave irradiation (100 W, 100° C.) for 30 min. Brown solid (0.020 g,23%). M.P.: 216-219° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.01 (d, J=2.9Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.59 (d, J=8.5 Hz, 1H), 8.26 (s, 1H),8.20 (d, J=8.6 Hz, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.77 (d, J=10.9 Hz,1H), 7.69 (s, 1H), 7.67 (dd, J=8.6, 4.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H),7.59 (d, J=8.0 Hz, 1H), 6.26 (s, 2H).

Example 2081-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanone

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.200 g, 0.676 mmol), 1-ethoxyvinyltri(n-butyl)stannane (0.244 g, 0.676 mmol), triphenylphosphine (0.0284g, 0.054 mmol), toluene (3.8 ml) and tris (dibenzilidineacetone)palladium(0) (0.028 g, 0.027 mmol) followed by acid hydrolysis. Brownsolid (0.080 g, 39%). ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.92 (d, J=3.0 Hz,1H), 8.49 (d, J=8.5 Hz, 1H), 8.15 (m, 3H), 7.94 (s, 1H), 7.87 (d, J=8.6Hz, 1H), 7.43 (dd, J=8.3, 4.2 Hz, 1H), 6.15 (s, 2H), 2.82 (s, 3H).

Example 2092-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)hydrazinecarboxamide

To a solution of example 208 (0.070 g, 0.230 mmol) in ethanol (2 ml),sodium acetate (0.018 g, 0.230 mmol) and semicarbazide hydrochloride(0.026 g, 0.230 mmol) were added and stirred at RT for 12 h. Thereaction mixture was concentrated and the residue was washed withbicarbonate solution, dichloromethane and dried under vacuum to affordthe title compound as a yellow solid (0.040 g, 48%). M.P.: 249-250° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.70 (s, 1H), 8.88 (d, J=2.8 Hz, 1H),8.54 (d, J=8.9 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H),8.01 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.81 (dd, J=8.6, 1.3 Hz, 1H), 7.53(dd, J=8.2, 4.1 Hz, 1H), 6.78 (br s, 2H), 6.14 (s, 2H), 2.35 (s, 3H).

Example 2104-(3-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-chlorobenzamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 38 (0.150 g, 0.496 mmol), intermediate 35(0.174 g, 0.620 mmol), potassium carbonate (0.228 g, 1.65 mmol), dioxane(3 ml), water (1 ml) and tetrakis(triphenylphosphine)palladium(0) (0.045g, 0.039 mmol) under microwave irradiation (100 W, 100° C.) for 30 min.Yellow solid (0.090 g, 43%). M.P.: 238-240° C. ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): 9.38 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.32 (s, 1H), 8.27 (s,1H), 8.25 (d, J=8.2 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.08 (d, J=8.4 Hz,1H), 7.97 (s, 1H), 7.69 (s, 1H), 7.64 (m, 2H), 6.18 (s, 2H).

Example 2112-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)propan-2-ol

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.150 g, 0.507 mmol), intermediate 19(0.177 g, 0.634 mmol), potassium carbonate (0.233 g, 1.68 mmol), dioxane(3 ml), water (0.6 ml) and tetrakis(triphenylphosphine)palladium(0)(0.047 g, 0.040 mmol). Pale green solid (0.080 g, 38%). M.P.: 85-89° C.¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 9.59 (s, 1H), 8.88 (d, J=2.7 Hz, 1H),8.67 (d, J=8.7 Hz, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.15 (m, 4H), 7.83 (m,2H), 7.53 (dd, J=8.1, 4.0 Hz, 1H), 6.21 (s, 2H), 5.38 (s, 1H), 1.51 (s,6H).

Example 2122-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was obtained as an off-white solid (0.065 g, 46%) byfollowing the procedure described for example 1 using intermediate 14(0.100 g, 0.338 mmol), intermediate 22 (0.118 g, 0.422 mmol), potassiumcarbonate (0.155 g, 1.12 mmol), DMF (8 ml), water (0.5 ml) andtetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol). M.P.:241-244° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 8.88 (dd, J=4.0, 2.6 Hz,1H), 8.69 (d, J=8.7 Hz, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.29 (s, 1H), 8.26(dd, J=11.6, 1.5 Hz, 1H), 8.20 (d, J=8.8 Hz, 1H), 8.03 (m, 3H), 7.83(dd, J=8.7, 1.6 Hz, 1H), 7.73 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.53 (dd,J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H).

Example 2133-(2-Chloro-3,6-difluorobenzyl)-5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine

The title compound was prepared by following the procedure described forexample 1 using intermediate 16 (0.180 g, 0.571 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.215 g, 0.731 mmol), potassium carbonate (0.260 g, 1.88 mmol), dioxane(3.5 ml), water (0.8 ml) and tetrakis(triphenylphosphine)palladium(0)(0.052 g, 0.044 mmol). Yellow solid (0.165 g, 83%). ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 13.22 (s, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.18 (s, 1H),7.82 (d, J=8.7 Hz, 1H), 7.63-7.51 (m, 2H), 7.45 (dt, J=9.2, 4.2 Hz, 1H),6.02 (s, 2H).

Example 2142-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 40 (0.450 g, 1.45 mmol), intermediate 35(0.511 g, 1.81 mmol), potassium carbonate (0.668 g, 3.33 mmol), dioxane(5 ml), water (1.5 ml) and tetrakis(triphenylphosphine)palladium(0)(0.134 g, 0.116 mmol) under microwave irradiation (100 W, 100° C.) for45 min. Off-white solid (0.250 g, 40%). M.P.: 140-143° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.87 (dd, J=3.8, 2.7 Hz, 1H), 8.68 (d, J=8.7 Hz, 1H),8.39 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 8.20 (m, 2H), 8.11 (s, 1H), 8.00(d, J=8.9 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.67 (s, 1H),7.60 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.4, 4.2 Hz, 1H), 6.73 (q, J=6.7 Hz,1H), 2.25 (d, J=7.0 Hz, 3H).

Example 2152-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-yl)benzamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 29 (0.150 g, 0.508 mmol), intermediate 35(0.179 g, 0.636 mmol), potassium carbonate (0.234 g, 1.69 mmol), dioxan(3 ml), water (1 ml) and tetrakis(triphenylphosphine) palladium(0)(0.047 g, 0.040 mmol) and in microwave oven (100 W, 100° C.) for 45 min.Off-white solid (0.095 g, 45%). M.P.: 212-214° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.87 (dd, J=4.1, 2.8 Hz, 1H), 8.73 (s, 1H), 8.35 (d,J=8.5 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.13 (d, J=8.1 Hz,1H), 8.01 (m, 3H), 7.90 (s, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.62 (s, 1H),7.55 (d, J=8.0 Hz, 1H), 7.53 (dd, J=8.6, 4.5 Hz, 1H), 5.78 (s, 2H).

Example 2161-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanoneoxime

To a solution of example 208 (0.060 g, 0.197 mmol) in ethanol (1.3 ml),sodium acetate (0.016 g, 0.197 mmol) and hydroxylamine hydrochloride(0.013 g, 0.197 mmol) were added and stirred at RT for 12 h. Thereaction mixture was concentrated and the residue was washed withbicarbonate solution, dichloromethane and dried under vacuum to affordthe title compound as a ca. 9:1 mixture of two isomers. Off-white solid(0.030 g, 48%). M.P.: 259-261° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):11.95 (s, 0.9H), 11.28 (s, 0.1H), 8.88 (d, J=2.6 Hz, 1H), 8.74 (d, J=8.8Hz, 0.1H), 8.61 (d, J=8.4 Hz, 0.1H), 8.52 (d, J=8.8 Hz, 0.9H), 8.36 (d,J=8.4 Hz, 0.9H), 8.00 (m, 3H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (dd,J=8.3, 4.1 Hz, 1H), 6.24 (s, 0.2H), 6.15 (s, 1.8H), 2.74 (s, 0.3H), 2.30(s, 2.7H).

Example 2171-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethanoneO-methyl oxime

The title compound was prepared as a ca. 9.5:0.5 mixture of two isomersby using a procedure similar to the one described for example 216 fromexample 208 (0.070 g, 0.230 mmol), ethanol (1.5 ml), sodium acetate(0.018 g, 0.230 mmol) and methoxylamine hydrochloride (0.019 g, 0.230mmol). Off-white solid (0.020 g, 26%). M.P.: 155-157° C. ¹H-NMR (δ ppm,DMSO-d₆, 400 MHz): 8.88 (d, J=2.6 Hz, 1H), 8.61 (d, J=8.8 Hz, 0.05H),8.55 (d, J=8.8 Hz, 0.95H), 8.36 (d, J=8.4 Hz, 1H), 8.02 (m, 3H), 7.81(dd, J=8.8, 1.7 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.16 (s, 2H),4.01 (s, 2.85H), 3.79 (s, 0.15H), 2.32 (s, 2.85H), 2.24 (s, 0.15H).

Example 218N′-(1-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)acetohydrazide

To a solution of example 208 (0.070 g, 0.230 mmol) in ethanol (1.3 ml),acetyl hydrazide (0.017 g, 0.230 mmol) was added refluxed for 4 h. Thereaction mixture was concentrated and the residue was washed with water,ethyl acetate and dried under vacuum to afford the title compound as aca. 1:1 mixture of two isomers. Pale yellow solid (0.035 g, 42%). M.P.:249-251° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 10.79 (s, 0.5H), 10.76 (s,0.5H), 8.89 (d, J=2.9 Hz, 1H), 8.66 (d, J=8.7 Hz, 0.5H), 8.55 (d, J=8.8Hz, 0.5H), 8.37 (m, 1.5H), 8.20 (d, J=9.0 Hz, 0.5H), 8.01 (m, 2H), 7.84(dt, J=9.0, 1.8 Hz, 1H), 7.54 (dd, J=8.3, 4.2 Hz, 1H), 6.20 (s, 1H),6.16 (s, 1H), 2.39 (s, 3H), 2.29 (s, 3H).

Example 2196-((5-(4-Methylpiperazin-1-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 152 using intermediate 14 (0.150 g, 0.507 mmol), N-methylpiperazine (0.076 g, 0.760 mmol), cesium fluoride (0.154 g, 1.01 mmol)and DMF (4.5 ml). Brown solid (0.023 g, 13%). M.P.: 131-133° C. ¹H-NMR(δ ppm, DMSO-d₆, 400 MHz): 8.87 (d, J=2.6 Hz, 1H), 8.35 (d, J=8.1 Hz,1H), 8.15 (d, J=9.3 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.93 (s, 1H), 7.74(d, J=8.5 Hz, 1H), 7.53 (dd, J=8.0, 4.0 Hz, 1H), 7.05 (d, J=9.4 Hz, 1H),5.89 (s, 2H), 3.68 (br. s, 4H), 2.42 (br.s, 4H), 2.22 (s, 3H).

Example 220N′-(1-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)ethylidene)isonicotinohydrazide

To a solution of example 208 (0.065 g, 0.214 mmol) in ethanol (1.5 ml),isonicotinic hydrazide (0.050 g, 0.428 mmol) was added refluxed for 12h. The reaction mixture was concentrated and the residue was washed withwater, ethyl acetate and dried under vacuum to afford the title compoundas a single isomer and as a pale yellow solid (0.070 g, 77%). M.P.:239-241° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz): 11.24 (s, 1H), 8.88 (dd,J=4.1, 2.5 Hz, 1H), 8.77 (s, 2H), 8.60 (br s, 1H), 8.37 (d, J=8.0 Hz,2H), 8.02 (d, J=8.8 Hz, 2H), 7.82 (d, J=7.1 Hz, 2H), 7.71 (m, 1H), 7.54(dd, J=8.3, 4.2 Hz, 1H), 6.18 (s, 2H), 2.55 (s, 3H).

Example 221(−)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The isomer was obtained through preparative SFC separation of theracemic compound i.e.(±)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide(0.24 g) on a CHIRALPAK IA column (250×30 mm; 5μ) using ethanol:CO₂(35:65) as the mobile phase at a flow rate of 70 g/min. Off-white solid(0.095 g). e.e. 96.84%. Rt: 4.27 min (CHIRALPAK IA column (250×4.6 mm;5μ) using ethanol: CO₂ (40:60) as the mobile phase at a flow rate of 3.0ml/min.). MP: 202-203° C. [α]_(D) ²³: −427.30 (c=1, CHCl₃). ¹H-NMR (δppm, CDCl₃+DMSO-d₆, 400 MHz): 8.88 (d, J=3.2 Hz, 1H), 8.43 (d, J=8.6 Hz,1H), 8.15 (d, J=6.1 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 8.00(d, J=8.4 Hz, 1H), 7.98 (s, 1H), 7.91 (m, 2H), 7.79 (d, J=8.6 Hz, 1H),7.40 (dd, J=8.2, 4.2 Hz, 1H), 6.62 (q, J=6.9 Hz, 1H), 6.54 (s, 1H), 6.12(s, 1H), 2.34 (d, J=7.1 Hz, 3H).

Example 222(+)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide

The isomers was obtained through preparative SFC separation of theracemic compound i.e.(±)-2-chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide(0.24 g) on a CHIRALPAK IA column (250×30 mm; 5μ) using ethanol:CO₂(35:65) as the mobile phase at a flow rate of 70 g/min. Off-white solid(0.035 g). e.e. 96.21%. Rt: 4.82 min (CHIRALPAK IA column (250×4.6 mm;5μ) using ethanol:CO₂ (40:60) as the mobile phase at a flow rate of 3.0ml/min.). MP: 200-202° C. ¹H-NMR (δ ppm, CDCl₃, 400 MHz): 8.90 (d, J=2.8Hz, 1H), 8.46 (d, J=8.6 Hz, 1H), 8.16 (m, 2H), 8.10 (d, J=8.7 Hz, 1H),8.13-7.95 (m, 3H), 7.92 (d, J=7.1 Hz, 1H), 7.81 (d, J=8.7 Hz, 1H), 7.42(dd, J=8.2, 4.2 Hz, 1H), 6.64 (q, J=7.0 Hz, 1H), 6.43 (s, 1H), 5.87 (s,1H), 2.36 (d, J=7.2 Hz, 3H).

Example 2234-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trifluoromethyl)benzamide

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.200 g, 0.676 mmol), intermediate 42(0.277 g, 0.879 mmol), potassium carbonate (0.311 g, 2.25 mmol), dioxane(4 ml), water (2 ml) and tetrakis(triphenylphosphine)palladium(0) (0.062g, 0.054 mmol) in a microwave oven (100 W, 100° C.) for 45 min. Brownsolid (0.035 g, 12%). M.P.: 230-232° C. ¹H-NMR (δ ppm, DMSO-d₆, 400MHz): 8.88 (d, J=2.9 Hz, 1H), 8.73 (d, J=8.7 Hz, 1H), 8.55 (d, J=5.5 Hz,1H), 8.52 (s, 1H), 8.35 (d, J=8.1 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.05(m, 3H), 7.84 (dd, J=10.2, 1.4 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.70 (s,1H), 7.54 (dd, J=8.3, 4.3 Hz, 1H), 6.24 (s, 2H).

Example 2246-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline1-oxide

To a solution of example 108 (0.100 g, 0.241 mmol) in acetone (0.6 ml),oxone (0.74 g, 1.20 mmol) in water (2 ml) was added and heated underreflux for 20 h. The mixture was diluted with aqueous 10% sodiumbicarbonate solution and extracted with dichloromethane, the organiclayer dried over anhydrous sodium sulphate and concentrated. The crudeproduct was purified by column chromatography withmethanol:dichloromethane to afford the title compound (0.030 g, 29%) asa pale brown solid. M.P.: 182-183° C. ¹H-NMR (δ ppm, DMSO-d₆, 400 MHz):8.71 (d, J=8.8 Hz, 1H), 8.55 (d, J=6.1 Hz, 1H), 8.52 (d, J=9.1 Hz, 1H),8.29 (s, 1H), 8.23 (m, 2H), 8.12 (s, 1H), 7.95-7.83 (m, 3H), 7.67 (s,1H), 7.61 (d, J=7.9 Hz, 1H), 7.47 (dd, J=8.4, 6.2 Hz, 1H), 6.24 (s, 2H).

Example 2252-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride

Ether saturated with HCl (1 ml) was added at 0° C. to a solution ofexample 119 (0.020 g. 0.045 mmol) in THF (1 ml), and stirred for 15 min.The precipitate formed was filtered, washed with ether and dried undervacuum to afford the title compound as an off-white solid (0.012 g,56%). M.P.: 151-153° C.

Example 2266-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline1-oxide

To a solution of example 119 (0.060 g, 0.135 mmol) in dichloromethane (1ml), 3-chloroperbenzoic acid (0.46 g, 0.270 mmol) was added and stirredat RT for 12 h. The mixture was diluted with water, extracted withdichloromethane, the organic layer dried over sodium sulphate andconcentrated. The crude product was purified by column chromatographywith methanol: dichloromethane as the eluent to afford the titlecompound as a grey solid. (0.016 g, 26%). M.P.: 212-215° C. ¹H-NMR (δppm, DMSO-d₆, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.68 (d, J=9.1 Hz, 1H),8.56 (m, 2H), 8.30 (d, J=1.5 Hz, 1H), 8.24 (m, 2H), 8.12 (s, 1H), 7.93(d, J=8.6 Hz, 1H), 7.86 (dd, J=9.1, 1.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H),7.48 (dd, J=8.4, 6.0 Hz, 1H), 6.20 (s, 2H), 3.28 (m, 2H), 1.14 (t, J=7.3Hz, 3H).

Example 2276-((5-(1H-pyrazol-4-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline

The title compound was prepared by following the procedure described forexample 1 using intermediate 14 (0.100 g, 0.338 mmol), tert-butyl3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(0.088 g, 0.422 mmol), potassium carbonate (0.155 g, 1.12 mmol), DMF (2ml), water (0.5 ml) and tetrakis(triphenylphosphine) palladium(0) (0.031g, 0.027 mmol) under microwave irradiation (100 W, 100° C.) for 45 min.Brown solid (0.025 g, 23%). M.P.: 215-218° C. ¹H-NMR (δ ppm, DMSO-d₆,400 MHz): 12.94 (s, 1H), 8.88 (dd, J=4.1, 1.5 Hz, 1H), 8.47 (d, J=8.7Hz, 1H), 8.36 (d, J=7.7 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J=7.9 Hz, 1H),8.00 (s, 1H), 7.79 (m, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H),2.56 (s, 3H).

Biological Assay

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The pharmacologicalassays which can be been carried out with the compounds according to theinvention and/or their pharmaceutically acceptable salts are exemplifiedbelow.

1. MET Kinase Assay Protocol:

Colorimetric Determination of c-Met Kinase Activity

The receptor tyrosine kinase c-Met is a heterodimeric transmembraneglycoprotein involved in several cellular processes that aid in tumorprogression. Phosphorylation of the tyrosine residues in the c-Metkinase domain is critical for its activity and the resulting down-streameffects. The colorimetric assay allows detection of the phosphorylatedform of a biotinylated peptide upon activation of human recombinant Metkinase.

MET Kinase Assay Protocol:

c-Met Kinase activity shall be determined using an HTScan® Met KinaseAssay Kit (Cell Signalling Technology, Beverly, Mass.) withmodifications. All incubations are carried out at room temperature.Briefly, 12.5 μl of a 4× reaction cocktail (DTT/Kinase buffer containingappropriate quantity of human Met kinase) is added to each well of a96-well plate containing 12.5 μl pre-diluted compound of interest andincubated for 5 minutes. After the initial incubation, 25 l/well of2×ATP/biotinylated peptide is added and incubated for an additional 30minutes. The reaction is terminated by the addition of 50 μl/well stopbuffer (50 mM EDTA, pH 8.0). The reaction mixture (25 μl/well) is thentransferred to a streptavidin coated plate (Perkin Elmer, Cat#4009-0010)containing 75 μl dH₂O and incubated for 60 minutes. The plate is washedwith 200 μl/well wash buffer (1×PBS, 0.05% Tween-20). After washing, 100μl/well phospho-tyrosine mAb (1:1000 in wash buffer containing 1% BSA)is added and incubated for 60 minutes. After another round of washes,100 μl/well europium labelled anti-mouse IgG (1:500 in wash buffercontaining 1% BSA) is added and incubated for an additional 30 minutes.Following additional washes, 100 μl/well Delfia® enhancement solution(Perkin Elmer, Cat#1244-105) is added and incubated for 45 minutes.Florescence is measured on a microplate reader (BMG Labtech., Germany)at 340 nm (excitation) and 615 nm (emission) for calculating %inhibition. Data generated can be analyzed further using Graphpad Prism(Graphpad software, San Diego Calif.) for determination of IC₅₀.

Results:

The results are as given below in Table 2 as % Inhibition of c-Met at 1μM.

TABLE 2 Cpd. Inhibition IC 50 Ex 2 A +++ Ex 6 A +++ Ex 8 A +++ Ex 9 A+++ Ex 13 A +++ Ex 14 A ++ Ex 15 A +++ Ex 16 A +++ Ex 21 B + Ex 52 A++++ Ex 108 A ++++ Ex 119 A ++++ Ex 130 A ++++ Ex 134 A ++++ Ex 137 A++++ Ex 221 A +++ Ex 222 B + A = ≥75 to 100 and B = ≥50-<75%; ++++ = ≤50nm; +++ = >50 to ≤100 nM; ++ = >100-≤250 and + = >251-≤1000 nM.

Inhibition of MKN-45 Proliferation:

Cell proliferation assays were carried out using the high Met expressinghuman gastric adenocarcinoma cell line, MKN-45, according to thefollowing schedule:

Day 1: Cells were plated in 96-well plates in complete growth medium.

Day 2: Compounds at desired concentrations were added.

Day 5: Cell viability was determined using the3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dyereduction test.

Results:

The results are as given below as % inhibition of mkn-45 proliferationat 1 μM in Table 3, at 0.1 μM in Table 3A and as GI₅₀ values in Table 4.

TABLE 3 % inhibition Cpd. @ 1 uM Ex 1 C Ex 18 D Ex 19 D Ex 22 D Ex 23 DEx 24 D Ex 25 D Ex 47 B Ex 48 A Ex 49 C Ex 51 D Ex 56 D Ex 58 D Ex 59 BEx 60 D Ex 61 A Ex 62 A Ex 63 B Ex 64 C Ex 65 D Ex 66 C Ex 67 13.83 Ex68 D Ex 69 D Ex 70 D Ex 71 C Ex 73 B Ex 74 B Ex 75 D Ex 76 B Ex 77 B Ex78 B Ex 79 B Ex 80 C Ex 81 A Ex 84 D Ex 85 A Ex 86 A Ex 87 D Ex 88 D Ex89 D Ex 90 A Ex 91 B Ex 92 D Ex 93 C Ex 94 D Ex 95 B Ex 96 D Ex 97 C Ex98 B Ex 99 B Ex 102 A Ex 104 A Ex 105 D Ex 106 A Ex 110 B Ex 111 A Ex114 B Ex 115 A Ex 116 A Ex 117 A Ex 118 A Ex 120 C Ex 121 D Ex 122 D Ex124 B Ex 125 D Ex 127 A Ex 137 B Ex 138 A Ex 139 D Ex 140 A Ex 141 A Ex147 D Ex 148 D Ex 150 D Ex 151 B Ex 167 C Ex 180 C Ex 181 A Ex 182 C Ex184 D Ex 185 D Ex 186 D Ex 190 D Ex 191 C Ex 192 D Ex 193 B Ex 194 B Ex195 B Ex 196 D Ex 212 C Ex 225 B Ex 226 D Ex 227 D D = <25%, C =≥25-<50%, B = ≥50-<75%, A = ≥75 to 100%

TABLE 3A Cpd Inhibition Ex 47 D Ex 48 D Ex 49 D Ex 51 D Ex 52 D Ex 55 DEx 56 D Ex 58 D Ex 59 D Ex 60 D Ex 61 A Ex 62 A Ex 63 D Ex 64 D Ex 65 DEx 66 D Ex 67 D Ex 68 D Ex 69 D Ex 70 D Ex 71 D Ex 72 D Ex 73 A Ex 74 BEx 75 D Ex 76 A Ex 77 B Ex 78 B Ex 79 D Ex 80 D Ex 81 B Ex 84 D Ex 85 DEx 86 D Ex 87 A Ex 88 D Ex 89 A Ex 90 B Ex 91 C Ex 92 D Ex 93 C Ex 94 BEx 95 D Ex 96 D Ex 97 C Ex 98 C Ex 99 B Ex 102 B Ex 103 D Ex 104 B Ex105 D Ex 106 D Ex 107 D Ex 108 B Ex 109 A Ex 110 B Ex 111 D Ex 113 A Ex114 B Ex 115 D Ex 116 D Ex 117 B Ex 118 D Ex 119 A Ex 120 A Ex 121 A Ex122 D Ex 123 B Ex 124 A Ex 125 D Ex 126 A Ex 127 A Ex 130 A Ex 133 A Ex134 B Ex 135 D Ex 137 A Ex 138 C Ex 139 B Ex 140 A Ex 141 A Ex 142 A Ex180 D Ex 181 D Ex 182 D Ex 183 D Ex 184 D Ex 185 D Ex 186 D Ex 187 A Ex188 A Ex 190 D Ex 191 C Ex 192 D Ex 193 D Ex 194 D Ex 195 C Ex 196 D Ex197 C Ex 198 D Ex 199 D Ex 200 D Ex 201 D Ex 202 D Ex 203 D Ex 212 A Ex206 B Ex 207 A Ex 209 A Ex 210 A Ex 214 A Ex 215 D Ex 216 D Ex 217 B Ex218 D Ex 219 D Ex 220 D Ex 221 B Ex 222 C Ex 223 A Ex 224 C Ex 225 A Ex226 D Ex 227 C D = <25%, C = ≥25-<50%, B = ≥50-<75%, A = ≥75 to 100%

TABLE 4 Cpd GI 50(nM) IC 50 (nM) Ex 2 E — Ex 4 C — Ex 6 C — Ex 8 E — Ex9 B B′ Ex 14 B B′ Ex 15 B B′ Ex 16 A A′ Ex 21 C — Ex 22 E — Ex 26 D — Ex27 B — Ex 28 C — Ex 30 C — Ex 31 C — Ex 32 D — Ex 33 C — Ex 34 D — Ex 35B — Ex 36 B — Ex 37 A — Ex 38 D — Ex 39 B — Ex 40 D — Ex 41 B — Ex 43 AB′ Ex 44 B — Ex 45 B — Ex 46 A B′ Ex 52 A A′ Ex 55 B — Ex 61 A — Ex 62 A— Ex 108 A A′ Ex 119 A A′ Ex 130 A A′ Ex 133 A Ex 134 A A′ Ex 137 A A′Ex 142 B — Ex 143 B — Ex 144 B — Ex 146 B B′ Ex 152 C — Ex 157 D — Ex164 B B′ Ex 168 C — Ex 169 D — Ex 170 D — Ex 171 C — Ex 172 D — Ex 173 D— Ex 175 C — Ex 176 D — Ex 177 D — Ex 179 C — Ex 187 A — Ex 188 B — Ex207 A — Ex 209 A — Ex 210 A — Ex 211 C — Ex 214 A — Ex 221 A — Ex 222 C— — A = A′ = ≤50; B = B′ = >50 to ≤150; C = >150-≤500; D = >500-≤1000 &E = >1000 in nM

Inhibition of c-Met Kinase Phosphorylation in MKN-45 Cells:

MKN45 cells are a prototype of “c-Met addicted” cells havingconstitutively activated c-Met kinase similar to that observed insub-sects of gastric or hepatocellular cancer patients with dysregulatedc-Met kinase activity. Inhibition of Met phosphorylation was determinedusing a cell based ELISA assay according to the following schedule:

Day 1: MKN-45 cells were plated in 96-well plates in complete growthmedium.

Day 2: Inhibitors at the desired concentration were added to the platesand incubated for 1 h and lysed subsequently.

Lysates were transferred to NUNC Maxisorp plates coated with anti-cMetreceptor antibody. Phopho-tyrosine mAb and HRP-lined anti-mouse IgG wereused as primary and secondary antibodies respectively. Optical densitywas measured on a microplate reader (BMG Labtech., Germany) at 450 nM.Inhibition of c-Met phosphorylation in this cell line indicates atherapeutic potential for test compounds in patients diagnosed withcancers caused by aberrant c-Met kinase signalling.

Results:

The results are provided above in Table 4 as IC50 values.

Inhibition of c-Met Kinase Phosphorylation in NCI-H441 Cells:

Inhibition of Met phosphorylation was determined using a cell basedELISA assay according to the following schedule:

Day 1: NCI-H441 cells were plated in 96-well plates in complete growthmedium.

Day 2: Inhibitors at the desired concentration were added to the plates,incubated for 1 h and lysed subsequently. Lysates were transferred toNUNC Maxisorp plates coated with anti-cMet receptor antibody.Phopho-tyrosine mAb and HRP-lined anti-mouse IgG were used as primaryand secondary antibodies respectively. Optical density was measured on amicroplate reader (BMG Labtech., Germany) at 450 nM. The compoundspotently inhibited c-Met kinase phosphorylation in NCI-H441, a non-smallcell lung cancer derived cell line indicating a therapeutic potential inlung cancer patients with mutant kras.

Results:

The results are given below in Table 5 as IC50 values.

TABLE 5 Cpd IC 50 Ex 146 +++ Ex 14 ++ Ex 15 ++ Ex 52 + Ex 108 + Ex 119 +Ex 139 + Ex 134 + Ex 137 + + = ≤10; ++′ = >10 to ≤50 +++ = >50-≤100 innM

Inhibition of Akt Phosphorylation in MKN-45 or NCI-H441 Cells:

Akt is a serine-threonine kinase and a downstream marker regulated byc-Met kinase via the PI3K pathway. Once phosphorylated, Akt regulatesseveral end processes including cell survival and growth. Cells weretreated with 0-1000 nM of test compounds, lysed, and the proteinsseparated on a 10% SDS-PAGE. Following separation, proteins weretransferred onto a nitrocellulose membrane and detected bychemiluminescence after incubation with pAkt S473 mAb (primary) andrabbit anti-mouse Ab (secondary). Intensity of the bands was determinedusing ImageJ 1.42q (NIH, USA) and normalized to Actin (loading control).

Results:

The results are provided below as IC50 values in Table 6.

TABLE 6 AKT PHOSPHORYLATION MKN-45 NCI-H441 Cpd (IC50-nM) (IC50-nM) Ex146 — B Ex 15 D A Ex 52 C A Ex 108 A A Ex 119 A A Ex 130 C B Ex 134 A AA = ≤25; B = >25 to ≤50, C = >50-≤100, D = >100-≤200 in nM,6. Induction of Apoptosis in MKN-45 Cells:

Induction of Caspase 3 was measured fluorimetrically. Cells wereincubated with desired concentrations of the compound for 24 h. Afterincubation, cells were harvested and counted. An equal number of viablecells per well (0.3×10⁶ cells) were used for determination of caspase-3activity. Increase in apoptosis manifested by an elevation in caspase-3levels was determined using a Caspase-3 kit from Millipore. Data areexpressed as a percent of the maximum response (100%). Compounds of theinvention dose-dependently induced apoptosis in MKN-45 cells manifestedby an increase in caspase-3 activity.

Results:

The results are provided below as percentage induction @ 3 μM in Table7.

TABLE 7 Apoptosis in Cpd MKN-45 cells) Ex 15 A Ex 52 A Ex 108 A Ex 119 AEx 130 B Ex 134 A B = ≤50, A = >50 to 100%7. Inhibition of HGF-Induced Met Phosphorylation in MDA-MB-231 Cells:

MDA-MB-231 is a breast cancer cell line having a high level of c-Metexpression. Activation of Met kinase in these cells occurs only afterthe addition of its natural ligand, Hepatocyte Growth Factor (HGF). Uponbinding to the extracellular domain of the enzyme, it triggersphosphorylation of tyrosine residues and regulates several downstreamevents such as cell proliferation. Cell proliferation assays werecarried out using the high Met expressing cell line (MDA-MB-231)according to the following schedule:

Day 1: Cells were plated in 96-well plates in complete growth medium.

Day 2: Media was replaced with starvation medium containing 0.04% BSA.

Day 3: Inhibitors at the desired concentrations and HGF (50 ng/ml) wereadded.

Day 5: Cell viability was determined using the3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dyereduction test.

The compounds of the present invention tested potently inhibitedHGF-induced Met phosphorylation in MDA-MB-231 cells thereby implicatingtheir role in the modulation of the HGF/Met axis in breast cancer.

Results:

The results are provided below in Table 8 as IC50 values.

TABLE 8 HGF stimulated Met Cpd phosphorylation Ex 15 + Ex 108 + Ex 119 +Ex 130 + Ex 134 ++ + = ≤10; ++ = >10 to ≤50 nM

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as described above and the claims.

All publications and patent and/or patent applications cited in thisapplication are herein incorporated by reference to the same extent asif each individual publication or patent application was specificallyand individually indicated to be incorporated herein by reference.

The invention claimed is:
 1. A method of inhibiting the HGF/c-Met kinasesignalling pathway in a cell comprising contacting the cell with acompound of formula (IA-1):

or a tautomer, stereoisomer, enantiomer, diastereomer, salt, or N-oxidethereof, wherein X is N; Cy₂ is selected from substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclicgroup, substituted aryl, and substituted or unsubstituted heteroaryl; Dis phenyl substituted with one to five substituents selected fromhalogen, substituted or unsubstituted alkyl, and —CONR^(x)R^(y); eachoccurrence of R^(x) and R^(y) is independently selected from hydrogen,hydroxy, halogen, carboxyl, cyano, nitro, oxo (═O), thio (═S),substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted cycloalkenyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted cycloalkenylalkyl,substituted or unsubstituted heterocycyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted arylalkyl, substituted or unsubstituted heteroaryl,substituted or unsubstituted heteroarylalkyl, —COOR^(z), —C(O)R^(z),—C(S)R^(z), —C(O)NR^(z)R^(z), —C(O)ONR^(z)R^(z), —NR^(z)R^(z),—NR^(z)CONR^(z)R^(z), —N(R^(z))SOR^(z), —N(R^(z))SO₂R^(z),—(═N—N(R^(z))R^(z)), —NR^(z)C(O)OR^(z), —NR^(z)C(O)R^(z)—,—NR^(z)C(S)R^(z)—NR^(z)C(S)NR^(z)R^(z), —SONR^(z)R^(z),—SO₂NR^(z)R^(z)—, —OR^(z), —OR^(z)C(O)NR^(z)R^(z), —OR^(z)(O)OR^(z)—,—OC(O)R^(z), —OC(O)NR^(z)R^(z), —R^(z)NR^(z)C(O)R^(z), —R^(z)OR^(z),—R^(z)C(O)OR^(z), —R^(z)C(O)NR^(z)R^(z), −R^(z)(O)R^(z),—R^(z)OC(O)R^(z), —SR^(z), −SOR^(z), —SO₂R^(z), and —ONO₂, or any two ofR^(x) and R^(y) which are directly bound to a common atom may be joinedto form (i) a substituted or unsubstituted, saturated or unsaturated3-14 membered ring, which may optionally include one or more heteroatomswhich may be the same or different and are selected from O, NR^(z) or S,or (ii) an oxo (═O), thio (═S) or imino (═NR^(z)); each occurrence ofR^(z) is independently selected from hydrogen, hydroxy, halogen,carboxyl, cyano, nitro, oxo (═O), thio (═S), substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted cycloalkenylalkyl, substituted or unsubstitutedheterocycyl, substituted or unsubstituted heterocyclyalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroarylalkyl, and —ONO₂, or any two of R^(z) which are directly boundto a common atom may be joined to form (i) a substituted orunsubstituted, saturated or unsaturated 3-14 membered ring, which mayoptionally include one or more heteroatoms which may be the same ordifferent and are selected from O, NR′ (where R′ is H or alkyl) or S, or(ii) an oxo (═O), thio (═S) or imino (═NR^(z)); R² is hydrogen; and L₂is —(CR^(a)R^(b))_(n)—; wherein each occurrence of R^(a) and R^(b) maybe the same or different and are independently selected from hydrogen,and methyl; each occurrence of R^(c) is independently selected fromhydrogen, nitro, hydroxy, cyano, halogen, substituted or unsubstitutedC₁₋₆ alkyl, substituted or unsubstituted C₂₋₆ alkenyl, substituted orunsubstituted C₂₋₆ alkynyl, substituted or unsubstituted C₃₋₆cycloalkyl, substituted or unsubstituted C₃₋₆ cycloralkylalkyl, andsubstituted or unsubstituted C₃₋₆ cycloalkenyl; and n is
 1. 2. Themethod of claim 1, wherein D is selected from


3. The method of claim 1, wherein each occurrence of R^(a) and R^(b) ishydrogen.
 4. The method of claim 1, wherein L₂ is —CH₂—, —CH(CH₃)— or—C(CH₃)₂—.
 5. The method of claim 1, wherein L₂ is —CH₂— or —CH(CH₃)—.6. The method of claim 1, wherein Cy₂ is substituted aryl or substitutedor unsubstituted bicyclic heteroaryl.
 7. The method of claim 1, whereinCy₂ is selected from


8. The method of claim 1, wherein Cy₂ is selected from


9. The method of claim 1, wherein the compound of formula (IA-1) isselected from(3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol;(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol;N-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanol;N-(2-Hydroxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;(4-Methylpiperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone;N-(2-(dimethylamino)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide;tert-Butyl4-(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)piperidine-1-carboxylate;N-(Piperidin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;N-(2-(dimethylamino)ethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-triazolo[4,5-b]pyridin-5-yl)benzamide;(S)-(2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanonehydrochloride;(4-(2-hydroxyethyl)piperazin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanone;(R)-(3-hydroxypyrrolidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanonehydrochloride;N-(2-(piperidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo-[4,5-b]pyridin-5-yl)benzamide;N-(2-morpholinoethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;(4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]-triazolo[4,5-b]pyridin-5-yl)phenyl)methanone;N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N,N-Bis(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)methanolhydrochloride;6-((5-(3-Fluoro-4-(methoxymethyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinolone;N-ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-cyclohexyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(pyridin-4-yl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Benzyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N,N-dimethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;Methyl2-(2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)acetate;2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamido)aceticacid;2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide;N-Methyl-3-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;6-((5-(3-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinolone;2-Fluoro-N-methoxy-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;N-tert-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Allyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;6-((5-(4-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinolone;6-((5-(2-Fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinolone;N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3-]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Ethyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;N-(3-(dimethylamino)-3-oxopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-(2-(dimethylamino)-2-oxoethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;6-((5-(4-(Cyclopropylcarbamoyl)-3-fluorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline1-oxide;N-Cyclopropyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;N-(Cyclopropylmethyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Butyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(furan-2-ylmethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(2,2,2-trifluoroethyl)benzamide;2-Fluoro-N-(2-methoxyethyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-isobutyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Cyclopentyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]-pyridin-5-yl)benzamide;2-Chloro-N-propyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-methyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Cyclobutyl-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-propyl-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Cyclopropyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Ethyl-2-fluoro-4-(3-(2-(quinolin-6-yl)propan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-N-methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-methoxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(thiazol-2-yl)benzamide;N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-N-cyclopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(3-oxo-3-(pyrrolidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-hydroxy-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-Isopropyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(3-oxo-3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-N-(3-morpholino-3-oxopropyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-(3-(dimethylamino)propyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidedihydrochloride;2-chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide;2-Chloro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;2-Fluoro-N-(3-(piperidin-1-yl)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;N-(3-Aminopropyl)-2-fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidedihydrochloride;2-Chloro-N-(3-(dimethylamino)propyl)-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidedihydrochloride;2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-N-(1H-1,2,4-triazol-3-yl)benzamidehydrochloride;2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-N-ethyl-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;3-(3-(Quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2,6-Difluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridine-5-yl)benzamidehydrochloride;2-Chloro-4-(3-((7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;2-Fluoro-4-(3-4(7-fluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;2-Methyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Fluoro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-4-(3-((5,7-difluoroquinolin-6-yl)methyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;4-(3-(Benzo[d]thiazol-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-chlorobenzamide;2-(2-Fluoro-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)phenyl)propan-2-ol;2-Chloro-5-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;(−)-2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;(+)-2-Chloro-4-(3-(1-(quinolin-6-yl)ethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamide;4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)-2-(trifluoromethyl)benzamide;6-((5-(4-carbamoyl-3-chlorophenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline1-oxide;2-chloro-N-ethyl-4-(3-(quinolin-6-ylmethyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-5-yl)benzamidehydrochloride;6-((5-(3-chloro-4-(ethylcarbamoyl)phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)methyl)quinoline 1-oxide; and pharmaceutically acceptable salts thereof.